A Single-site, Open-label, Non-comparator Clinical Trial to eLiminate HCV-infection in Treatment-naïve, EgyptiAn Patients With End-stage Renal Disease on Renal Dialysis, With Chronic Hepatitis C Genotype 4 Infection Using a 12-week Course of Once-daily Single Oral Tablet of Elbasvir (50mg)/Grazoprevir (100 mg)

Primary Efficacy Objective
-To assess whether a 12-week treatment course with oral 50 mg elbasvir plus 100 mg grazoprevir given in a single daily dose to treatment-naïve patients with end-stage renal disease (ESRD) and infected with genotype 4 (GT4) chronic HCV (CHC) infection can produce a sustained viral response (SVR), i.e. HCV RNA below the lower limit of quantification [LLOQ] for 12 weeks (SVR12) after completion of the study treatment course
Secondary Objectives
To assess the efficacy of elbasvir/grazoprevir in suppressing HCV viremia in treatment-naïve GT4 CHC patients at each scheduled visit and clinically meaningful endpoints (Week 2, 8 and 12 [End of Treatment - EOT]) and 24 (SVR12)
To assess the safety and tolerability of a 12-week treatment course with elbasvir/grazoprevir in treatment-naïve patients with ESRD and infected with GT4 CHC.
To assess liver fibrosis by non-invasive evaluation of liver stiffness (Fibroscan®) in the same patients before treatment and EOT and SVR12
Clinical hypotheses.
Primary Efficacy Hypothesis
- A 12-week treatment course with elbasvir/grazoprevir in treatment-naïve patients with ESRD and infected with GT4 CHC infection will result in an HCV RNA below the LLOQ in 95% of patients within 2 weeks of treatment, and at least 95% will have an SVR12.
Secondary hypotheses
A 12-week treatment course with elbasvir/grazoprevir in ESRD GT4 treatment-naïve patients will result in undetectable viremia in 95% patients at Week 2, 4, 8 and 12 (EOT) and 24 (SVR12)
Treatment will be safe and well-tolerated in these patients, as determined by the type and number of adverse events identified through laboratory testing, vital signs and physical examinations.
In these patients with liver fibrosis before treatment, the liver fibrosis as assessed by non-invasive evaluation of liver stiffness (Fibroscan®) will improve by EOT and SVR12

Start Date01 Dec 2019

Sponsor / Collaborator

University of Maryland Baltimore

[+2]

NCT03365635

/ CompletedPhase 4IIT

"Real World" Administration of Zepatier (Grazoprevir Plus Elvasvir) in Chronic Hemodialysis Patients With Hepatitis C Infection. Strategies for Identification of Patients, Insurance Approval, Treatment , and Laboratory Monitoring

This is a study to define strategies for Nephrologists to directly supervise and apply direct acting antivirals to cure hepatitis C in hemodialysis patients. Strategies will include identification of candidate patients, application for insurance approval, specifics of direct acting antiviral therapy (Zepatier with or without ribavirin) and laboratory monitoring during and after therapy.

Start Date22 Sep 2019

Sponsor / Collaborator

University of Pennsylvania

[+1]

NCT04048850

/ Unknown statusNot ApplicableIIT

Cohort Study of Hepatitis C Virus Treatment With Zepatier (Elbasvir/Grazoprevir) in Genotype 1 or 4 HCV Treatment-Naïve or Peginterferon/Ribavirin-Experienced Patients With Substance Use in Urban, Multidisciplinary Specialty Clinics

The goal of this study is to assess hepatitis C virus (HCV) treatment with Zepatier (elbasvir/grazoprevir) in HCV monoinfected and human immunodeficiency virus (HIV)-HCV co-infected, HCV treatment-naïve or peginterferon/ribavirin-experienced patients with HCV genotype 1a, without baseline NS5A resistance, 1b, or 4 and substance use in urban, multidisciplinary specialty clinics.

Start Date20 Sep 2019

Sponsor / Collaborator

University of Illinois

[+1]

100 Clinical Results associated with Elbasvir/Grazoprevir

100 Translational Medicine associated with Elbasvir/Grazoprevir

100 Patents (Medical) associated with Elbasvir/Grazoprevir

Literatures (Medical) associated with Elbasvir/Grazoprevir

01 Oct 2022·Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology

Full-genome next-generation sequencing of hepatitis C virus to assess the accuracy of genotyping by the commercial assay LiPA and the prevalence of resistance-associated substitutions in a Belgian cohort

Article

Author: Vandamme, Anne-Mieke ; Simmonds, Peter ; Dierckx, Tim ; Beuselinck, Kurt ; Schrooten, Yoeri ; Bonsall, David ; Bowden, Rory ; Lagrou, Katrien ; Christensen, Kasper T ; Pierard, Florian ; Cuypers, Lize ; Van Laethem, Kristel ; Nevens, Frederik ; Van Wijngaerden, Eric

BACKGROUND:

Although most currently used regimens for Hepatitis C virus (HCV) infections can be initiated without prior knowledge of genotype and subtype, genotyping is still useful to identify patients who might benefit from a personalized treatment due to resistance to direct-acting antivirals (DAA).

OBJECTIVES:

To assess the utility of full-genome next-generation sequencing (FG-NGS) for HCV genotyping.

STUDY DESIGN:

138 HCV plasma samples previously genotyped by VERSANT HCV Genotype Assay (LiPA) were subjected to FG-NGS and phylogenetically genotyped Genome Detective. Consensuses were analysed by HCV-GLUE for resistance-associated substitutions (RASs) and their impact on treatment response was investigated.

RESULTS:

102/138 (73.9%) samples were sequenced to a genome coverage and depth of >90% of the HCV open reading frame covered by >100 reads/site. Concordant genotype and subtype results were assigned in 97.1% and 79.4% of samples, respectively. FG-NGS resolved the subtype of 13.7% samples that had ambiguous calls by LiPA and identified one dual infection and one recombinant strain. At least one RAS was found for the HCV genes NS3, NS5A, and NS5B in 2.91%, 36.98% and 27.3% samples, respectively. Irrespective of the observed RAS, all patients responded well to DAA treatment, except for HCV1b-infected patients treated with Zepatier (33.3% failure rate (5/15)).

CONCLUSION:

While LiPA and FG-NGS showed overall good concordance, FG-NGS improved specificity for subtypes, recombinant and mixed infections. FG-NGS enabled the detection of RAS, but its predictive value for treatment outcome in DAA-naïve patients remains uncertain. With additional refinements, FG-NGS may be the way forward for HCV genotyping.

01 Jul 2022·Dermatologic therapy

Cardiac conduction block during secukinumab treatment

Letter

Author: Tang, Xin ; Huang, Kun ; Zheng, Xuyu ; Hu, Li ; Wang, Ping ; Chen, Aijun

Psoriasis is an immune-mediated chronic inflammatory skin disease and IL-17A is a cornerstone of the pathogenesis of psoriasis.Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, is effective in treating moderate to severe psoriasis.This article reports a rare case of cardiac conduction block occurring during the treatment with secukinumab.A man in his 30s presented with moderate and severe psoriasis vulgaris, and the body surface area was above 30%.He was commenced on secukinumab therapy for psoriasis and Zepatier (elbasvir and grazoprevir) for hepatitis C.The treatment with secukinumab continued, and after 3 mo, the remission of all skin lesions was obtained and the patient frequently experienced dizziness, headache, and palpitation.In this case, some factors might relate to cardiac conduction block, such as underlying heart disease, hepatitis C, and drugs.Some cardiac disorders, as a rare adverse events, have been observed in the real-world clin. trials, including tachycardia, atrioventricular first-degree block, and sinus bradycardia.Thus, authors are still in the early stages of exploring the effect of secukinumab on the heart.

01 May 2022·Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology AssociationQ4 · MEDICINE

The efficacy of Elbasvir/Grazoprevir fixed-dose combination for 8 weeks in HCV treatment and health-related quality of life (HRQoL) in treatment-naïve, non-cirrhotic, genotype 4-infected patients (ELEGANT-4)

Q4 · MEDICINE

ArticleOA

Author: Alamr, Abdulrahman ; AlGhamdi, Adel ; Al Ibrahim, Bashaar ; Ahmad, Shameem ; AlKhathlan, Abdullah ; Al Sayari, Khalid ; Al Otaibi, Nawwaf ; Qutub, Adel ; Abbarh, Shahem ; Al Balkhi, Areej ; Almtawa, Abdullah ; AlEid, Ahmad ; AlLehibi, Abed ; AlGhamdi, Ahmed

Background::

Cost, adverse events, and long treatment duration can be significant obstacles in treating hepatitis C virus (HCV)-infected individuals. Shortening the treatment regimen can minimize these barriers, thereby enhancing adherence and increasing medication availability to more patients.

Methods::

This is a single-centre, single-arm, open-label, phase 3 clinical trial on treatment naïve, non-cirrhotic, HCV genotype 4 patients. The study aimed to evaluate an 8-week course of Elbasvir (ELB)/Grazoprevir (GZR) in this population. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment (SVR-12). The secondary endpoints were SVR-4, adverse events, and changes in health- and hepatitis-related quality of life (HRQoL).

Results::

Of the 30 patients who were enrolled, 29 (97%) achieved SVR-12 and SVR-4 (95% CI: 90-100%). No patients experienced serious or life-threatening adverse events (AEs), but mild/moderate AEs were reported by 16 (53%). The most commonly reported AEs were itching/skin rash (20%), headache (16.7%), abdominal/epigastric pain and decreased appetite (13.3% each), and nausea/vomiting (10%). Marked improvements in HRQoL were reported between the first (baseline) and third (SVR-12) timepoints. HRQoL score improvements involved the physical, mental, and hepatitis-specific indices, and ranged between 6 and 42 points (out of 100, P ≤0.003).

Conclusion::

The trial provides empirical evidence that HCV genotype 4-infected patients can achieve viral eradication with an 8-week-regimen of ELB/GZR. Further, this course of treatment is associated with a minimal adverse event profile and potentially significant improvements in quality of life. (ClinicalTrials.gov number, NCT03578640).

News (Medical) associated with Elbasvir/Grazoprevir

21 Jun 2024

·www.biospace.com

Aprea Therapeutics to Host Virtual KOL Event on APR-1051, a Highly Selective and Potentially Best-in-Class Oral WEE1 Inhibitor, on Monday, June 24, 2024

DOYLESTOWN, Pa., June 21, 2024 (GLOBE NEWSWIRE) -- Aprea Therapeutics, Inc. (Nasdaq: APRE) (“Aprea”, or the “Company”), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, today announced that it will host a virtual KOL event to discuss APR-1051, a highly selective and potentially best-in-class oral WEE1 inhibitor, on Monday, June 24, 2024 at 9:00 AM ET. To register, click here. The webinar will feature Joseph Vacca, PhD, Medicinal Chemistry Expert and Consultant to Aprea, who will discuss the medicinal chemistry history, highly selective drug design, and preclinical findings of APR-1051. It will also feature Eric J. Brown, PhD (University of Pennsylvania) who will discuss preclinical findings across the WEE1 inhibitor class. WEE1 is an enzyme involved in the DNA damage response pathway and is a validated oncology target. APR-1051 is a potent and selective small molecule that has been designed to limit off-target toxicity. Aprea recently initiated the Phase 1 ACESOT-1051 trial evaluating APR-1051 as monotherapy treatment in patients with significant unmet medical need, including patients with Cyclin E over expression. A live question and answer session will follow the formal presentations. Joseph Vacca, PhD is a medicinal chemist who spent 30 years at Merck Research Laboratories (1981 to 2011). He and his teams made major contributions to several approved drugs including the HIV protease inhibitor CRIXIVAN™ (indinavir sulfate), the HIV integrase inhibitor Isentress™ (raltegravir); the HCV protease Inhibitor (Vanihep™, vaniprevir), the combination product Zepatier™ which is a combination of the second generation HCV protease Inhibitor grazoprevir and the NS5A protein Inhibitor elbasvir and the recently approved second generation HIV NNRTI inhibitor doravirine. Upon his retirement from Merck in 2011, Dr. Vacca took a role as Senior Vice President of Early Success Sharing Partnerships at WuXi AppTec Limited. He left WuXi in September 2015 to be a consultant and now acts as an interim head of chemistry for several small startup companies. Dr. Vacca has over 100 publications and patents and is the holder of many awards including a Merck Directors Award (1998); PhRMA Discoverers Award (1999); Intellectual Property Owners “National Inventor of the year Award” (1997); European Inventor of the Year (non-EU nation) (2007); ACS “Award for Creative Invention” (1999); and was a named a Merck Research Laboratories Presidential Fellow in 2008. He was named to the American Chemical Society Medicinal Chemistry Hall of Fame (Aug. 2012) and was also named a “Hero of Chemistry” (along with the research team) for his role in the discovery and development of the HIV integrase inhibitorIsentress™. Dr. Vacca earned a BS in chemistry in 1977 from St. John Fisher College, Rochester, New York, and obtained a PhD degree in Organic Chemistry under Professor Peter T. Lansbury Sr. at the State University of New York at Buffalo (New York). Eric J. Brown, PhD is Associate Professor of Cancer Biology at the University of Pennsylvania and a Scientific Consultant to Aprea Therapeutics. Dr. Brown’s laboratory at Penn focuses on the role of the replication stress response on genome stability. His research seeks to identify the cancer-associated genetic changes that increase the efficacy of therapeutics that abrogate replication stress responses, such as ATR and WEE1 inhibitors. The genetic changes that impact sensitivity to these therapies are identified through various orthogonal approaches, including proteomics, genome-wide breakpoint mapping, and computational methods. Overall, the goal of this research is both to better understand the mechanism by which these cancer therapeutics operate and to improve responses to these treatments in patients. About Aprea Aprea Therapeutics, Inc. is a clinical-stage biopharmaceutical company headquartered in Doylestown, Pennsylvania, focused on precision oncology through synthetic lethality. The Company’s lead program is ATRN-119, a clinical-stage small molecule ATR inhibitor in development for solid tumor indications. APR-1051, an oral, small molecule WEE1 inhibitor, recently entered the clinic. For more information, please visit the company website at . The Company may use, and intends to use, its investor relations website at as a means of disclosing material nonpublic information and for complying with its disclosure obligations under Regulation FD. Forward-Looking Statement Certain information contained in this press release includes “forward-looking statements”, within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended related to our study analyses, clinical trials, regulatory submissions, and projected cash position. We may, in some cases use terms such as “future,” “predicts,” “believes,” “potential,” “continue,” “anticipates,” “estimates,” “expects,” “plans,” “intends,” “targeting,” “confidence,” “may,” “could,” “might,” “likely,” “will,” “should” or other words that convey uncertainty of the future events or outcomes to identify these forward-looking statements. Our forward-looking statements are based on current beliefs and expectations of our management team and on information currently available to management that involve risks, potential changes in circumstances, assumptions, and uncertainties. All statements contained in this press release other than statements of historical fact are forward-looking statements, including statements regarding our ability to develop, commercialize, and achieve market acceptance of our current and planned products and services, our research and development efforts, including timing considerations and other matters regarding our business strategies, use of capital, results of operations and financial position, and plans and objectives for future operations. Any or all of the forward-looking statements may turn out to be wrong or be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. These forward-looking statements are subject to risks and uncertainties including, without limitation, risks related to the success, timing, and cost of our ongoing clinical trials and anticipated clinical trials for our current product candidates, including statements regarding the timing of initiation, pace of enrollment and completion of the trials (including our ability to fully fund our disclosed clinical trials, which assumes no material changes to our currently projected expenses), futility analyses, presentations at conferences and data reported in an abstract, and receipt of interim or preliminary results (including, without limitation, any preclinical results or data), which are not necessarily indicative of the final results of our ongoing clinical trials, our understanding of product candidates mechanisms of action and interpretation of preclinical and early clinical results from its clinical development programs, and the other risks, uncertainties, and other factors described under “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and elsewhere in the documents we the U.S. Securities and Exchange Commission. For all these reasons, actual results and developments could be materially different from those expressed in or implied by our forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of the date of this press release. We undertake no obligation to update such forward-looking statements for any reason, except as required by law. Investor Contact: Mike Moyer LifeSci Advisors mmoyer@lifesciadvisors.com

Phase 1Executive Change

28 Feb 2024

·www.biospace.com

ViiV Healthcare to present data for its next generation of ultra long-acting treatments for HIV

Other key data to be presented from ViiV Healthcare’s innovative pipeline and portfolio include the exploration of different mechanisms of action through broadly neutralising antibodies as well as real-world insights from established long-acting and 2-drug regimens LONDON--(BUSINESS WIRE)-- ViiV Healthcare, the global specialist HIV company majority owned by GSK, with Pfizer and Shionogi as shareholders, today announced the presentation of 64 abstracts that includes highlights of the company’s next-generation pipeline advancements, alongside data from its diverse portfolio of marketed HIV treatment and prevention options at the Conference on Retroviruses and Opportunistic Infections (CROI 2024) being held in Denver, Colorado, from 3 – 6 March 2024. Kimberly Smith, M.D., MPH, Head of Research & Development at ViiV Healthcare, said: “As leaders in developing long-acting injectables for the treatment of HIV, we’re excited to present new data setting the stage for ViiV’s next generation of medicines and demonstrating how key pipeline assets will target HIV in different ways. These findings, as well as the breadth of data we’ll present on our marketed products, including new interim results from the LATITUDE study, reflect a portfolio and future-looking pipeline focused on ending the HIV epidemic. We look forward to sharing them with the scientific and HIV communities at CROI 2024.” Key abstracts to be presented at CROI 2024 by ViiV Healthcare and its study partners will include: Data introducing our next generation of potential ultra long-acting medicines for HIV: ViiV Healthcare will share findings from a phase I study evaluating different formulations of cabotegravir and their potential for dosing every four months. The ongoing, open-label, single-dose, dose-escalation phase I study in 70 healthy adults assessed both the 200 mg/mL formulation of cabotegravir in combination with recombinant human hyaluronidase PH20 (rHuPH20), as well as a new formulation of cabotegravir (CAB ULA) administered by itself.1 Researchers will share safety and pharmacokinetic findings from both ultra long-acting approaches and their potential for future clinical development. Findings advancing different mechanisms of action in HIV research: New phase IIa findings from the BANNER study of VH3810109 (N6LS), an investigational, broadly neutralising antibody (bNAb), will be presented. Researchers will share findings of the bNAb administered intravenously and the first efficacy findings of its subcutaneous administration.2 Findings from the SPAN study of N6LS, examining the safety and tolerability of the highest subcutaneous and intravenous N6LS doses administered to date, with and without PH20, will also be presented.3 Additionally, efficacy and safety data from a non-ViiV owned bNAb asset, VRC07-523LS, in a phase II, open-label clinical trial used in combination with long-acting CAB for maintenance antiretroviral therapy (ART) will be presented.4 New data on long-acting therapy vs daily oral standard of care, in traditionally non-adherent populations: Interim analysis of the LATITUDE phase III trial will be presented showing that, the injectable antiretroviral treatment for HIV, Cabenuva (cabotegravir and rilpivirine [CAB+RPV LA]), demonstrates superior efficacy compared to daily oral standard of care (SOC) in individuals with a history of antiretroviral adherence challenges. The NIAID/ACTG also announced a modification to the study, where further randomisation has been stopped and participants in the SOC arm are being given the option to switch to the long-acting therapy arm.5 Real-world evidence from across our treatment and prevention portfolios: New findings from SEARCH, a randomised study evaluating the real-world impact of the inclusion of long-acting cabotegravir for PrEP in an HIV prevention coverage package compared to the standard-of-care of oral PrEP and PEP alone in rural Uganda and Kenya, will also be presented.6 Real-world evidence findings for the complete long-acting HIV treatment regimen Cabenuva will be presented from the OPERA cohort examining ART-experienced, virally suppressed adults living with HIV who switched to CAB+RPV LA or to an oral regimen.7 Findings for the 2-drug regimen, Dovato (dolutegravir, lamivudine [DTG/3TC]), will include the InfCare HIV study, which presents three-year switch data, from 3-drug regimen to Dovato, in a long-term real-world Swedish cohort.8 This study adds to the body of real-world evidence to date that includes more than 40,000 people living with HIV.9 Here is a list of ViiV Healthcare-sponsored or supported studies to be presented at CROI 2024: Title First Author Presentation Number Presentation Dolutegravir A single once-daily ABC/DTG/3TC tablet predicts safe and effective exposures in children 3 to <6kg H. Chandasana 02770 Poster Tuesday, March 5 2:30-4:00pm MST Population pharmacokinetics of ABC/DTG/3TC FDC to support dosing in peds with HIV-1 (IMPAACT 2019) H. Chandasana 03110 Poster Tuesday, March 5:30-4:00pm MST Dolutegravir and growth in pediatric populations with HIV-1: IMPAACT P1093 and IMPAACT 2019 M. McKenna 01783 Poster Tuesday, March 5 2:30-4:00pm MST Switching to DTG+3TC vs 3-drug regimens in routine clinical care: long-term Swedish data E. Sörstedt 01838 Poster Tuesday, March 5 2:30-4:00pm MST Temporal trends of cardiovascular disease incidence in people with HIV from 2001-2021 N. Jaschinski 02263 Poster Tuesday, March 5 2:30-4:00pm MST Increased cancer risk with low CD4 counts persists despite over 2 years of virological suppression J. Hoy 01462 Poster Wednesday, March 6 2:30-4:00pm MST Cabotegravir for Treatment Long-acting Injectable CAB/RPV is Superior to Oral ART in PWH with adherence challenges: ACTG A5359 A. Rana 03579 Oral Wednesday, March 6 12:51-1:00pm MST Real-world utilization of cabotegravir + rilpivirine in the US: data from Trio Health cohort J. J. Eron 01374 Poster Monday, March 4 2:30-4:00pm MST Real-world effectiveness of cabotegravir + rilpivirine vs. standard of care oral regimens in the US R. K. Hsu 01952 Poster Monday, March 4 2:30-4:00pm MST HIV-1 RNA blips and low-level viral replication: SOLAR (CAB+RPV LA vs. BIC/FTC/TAF) C. Latham 00138 Poster Monday, March 4 2:30-4:00pm MST Model based comparison of cabotegravir pharmacokinetics following thigh and gluteal injections K. Han 03157 Poster Wednesday, March 6 2:30-4:00pm MST Cabotegravir for PrEP SEARCH Randomized trial of Dynamic Choice HIV Prevention including injectable cabotegravir (CAB-LA) J. Kabami 03405 Late-Breaker Oral Tuesday, March 5 10:00-12:00pm MST Pre-exposure prophylaxis with cabotegravir long-acting injectable in the OPERA cohort A. Mills 01400 Poster Monday, March 4 2:30-4:00pm MST Real-world use of cabotegravir long acting for pre-exposure prophylaxis: TRIO cohort K. Mayer 01907 Poster Monday, March 4 2:30-4:00pm MST Cabotegravir PopPK analysis of adults and adolescents living with HIV or at risk for HIV receiving PrEP Y. Lin 03038 Poster Tuesday, March 5 2:30-4:00pm MST Interest in long-acting injectable PrEP among transgender women in the United States E. E. Cooney 00621 Poster Wednesday, March 6 2:30-4:00pm MST Healthcare staff acceptability and feasibility of telehealth delivery of cabotegravir for PrEP A. Liu 03080 Poster Wednesday, March 6 2:30-4:00pm MST Fostemsavir Temsavir treatment enhances bNAb recognition and subsequent clearance of HIV-1 infected cells R. Ferris 02971 Poster Monday, March 4 2:30-4:00pm MST Pipeline: Ultra Long-Acting Cabotegravir Phase I study of cabotegravir long-acting injectable formulations supports ≥4-monthly dose interval K. Han 00251 Oral Monday, March 4 10:00-12:00pm MST Pipeline: Broadly Neutralising Antibodies VH3810109 (N6LS) in antiretroviral therapy–naive adults with HIV-1: phase IIa BANNER efficacy data P. Leone 01911 Oral Monday, March 4 10:00-12:00pm MST Safety and efficacy of VRC07-523LS plus long-acting cabotegravir in the phase 2 ACTG A5357 Trial B. Taiwo 02254 Oral Monday, March 4 10:00-12:00pm MST High-dose VH3810109 (N6LS) ± recombinant human hyaluronidase PH20: phase I SPAN study safety results B. Win 01988 Poster Wednesday, March 6 2:30-4:00pm MST Pipeline: Maturation Inhibitors Next-generation maturation inhibitor GSK3640254 showed broad spectrum potency without MI resistance B. McAuliffe 03095 Poster Wednesday, March 6 2:30-4:00pm MST The preclinical pro maturation inhibitor VH3739937 J. Jeffrey 02819 Poster Wednesday, March 6 2:30-4:00pm MST General HIV Resistance in young children newly diagnosed with HIV in Western Cape, South Africa K. Anderson 01012 Poster Tuesday, March 5 2:30-4:00pm MST DOVATO (dolutegravir and lamivudine) tablets INDICATION Dovato is indicated as a complete regimen to treat HIV-1 infection in adults with no antiretroviral (ARV) treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ARV regimen with no history of treatment failure and no known resistance to any component of Dovato. IMPORTANT SAFETY INFORMATION BOXED WARNING: PATIENTS CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV-1: EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND EXACERBATIONS OF HBV All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating Dovato. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If Dovato is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen. Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of Dovato. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment. CONTRAINDICATIONS Do not use Dovato in patients with previous hypersensitivity reaction to dolutegravir or lamivudine Do not use Dovato in patients receiving dofetilide WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury Discontinue Dovato immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated Hepatotoxicity: Hepatic adverse events have been reported, including cases of hepatic toxicity (elevated serum liver biochemistries, hepatitis, and acute liver failure), in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of Dovato. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn Monitoring for hepatotoxicity is recommended Embryo Fetal Toxicity: Assess the risks and benefits of Dovato and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy due to the risk of neural tube defects Pregnancy testing is recommended before initiation of Dovato. Individuals of childbearing potential should be counseled on the consistent use of effective contraception Lactic Acidosis and Severe Hepatomegaly With Steatosis: Fatal cases have been reported with the use of nucleoside analogs, including lamivudine. Discontinue Dovato if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations. Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of Dovato and other drugs may occur (see Contraindications and Drug interactions). Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of Dovato. Adverse reactions The most common adverse reactions (incidence ≥2%, all grades) with Dovato were headache (3%), nausea (2%), diarrhea (2%), insomnia (2%), fatigue (2%), and anxiety (2%). Drug interactions Consult full Prescribing Information for Dovato for more information on potentially significant drug interactions Dovato is a complete regimen. Coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended Drugs that induce or inhibit CYP3A or UGT1A1 may affect the plasma concentrations of dolutegravir Administer Dovato 2 hours before or 6 hours after taking polyvalent cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, Dovato and supplements containing calcium or iron can be taken with food Use in specific populations Pregnancy: There are insufficient human data on the use of Dovato during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established. Advise individuals of childbearing potential of the potential risk of neural tube defects. Assess the risks and benefits of Dovato and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in a breastfed infant Females and Males of Reproductive Potential: Pregnancy testing is recommended before initiation of Dovato. Counsel individuals of childbearing potential taking Dovato on the consistent use of effective contraception Renal Impairment: Dovato is not recommended for patients with creatinine clearance <30 mL/min. Patients with a sustained creatinine clearance between 30 and 49 mL/min should be monitored for hematologic toxicities, which may require a dosage adjustment of lamivudine as an individual component Hepatic Impairment: Dovato is not recommended in patients with severe hepatic impairment (Child-Pugh Score C) For more information, please see full US Prescribing Information for Dovato: https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Dovato/pdf/DOVATO-PI-PIL.PDF CABENUVA (cabotegravir; rilpivirine) extended-release injectable suspensions INDICATION CABENUVA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Do not use CABENUVA in patients with previous hypersensitivity reaction to cabotegravir or rilpivirine Do not use CABENUVA in patients receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone (>1 dose), and St John’s wort WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA Hypersensitivity reactions, including cases of drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during postmarketing experience with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop. Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. Cabotegravir and rilpivirine oral lead-in may be used to help identify patients who may be at risk of a hypersensitivity reaction Post-Injection Reactions: Serious post-injection reactions (reported in less than 1% of subjects) were reported within minutes after the injection of rilpivirine, including dyspnea, bronchospasm, agitation, abdominal cramping, rash/urticaria, dizziness, flushing, sweating, oral numbness, changes in blood pressure, and pain (e.g., back and chest). These events may have been associated with accidental intravenous administration and began to resolve within a few minutes after the injection Carefully follow the Instructions for Use when preparing and administering CABENUVA. The suspensions should be injected slowly via intramuscular injection and avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a post-injection reaction occurs, monitor and treat as clinically indicated Hepatotoxicity: Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected Depressive Disorders: Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation, suicide attempt) have been reported with CABENUVA or the individual products Promptly evaluate patients with depressive symptoms Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions (see Contraindications and Drug Interactions) Rilpivirine doses 3 and 12 times higher than the recommended oral dosage can prolong the QTc interval CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes Long-Acting Properties and Potential Associated Risks with CABENUVA: Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). Select appropriate patients who agree to the required monthly or every-2-month injection dosing schedule because non-adherence could lead to loss of virologic response and development of resistance To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA when dosed monthly and no later than 2 months after the final injections of CABENUVA when dosed every 2 months. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible ADVERSE REACTIONS The most common adverse reactions in adults (incidence ≥2%, all grades) treated with CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash The safety of CABENUVA in adolescents is expected to be similar to adults DRUG INTERACTIONS Refer to the applicable full Prescribing Information for important drug interactions with CABENUVA, VOCABRIA (cabotegravir), or EDURANT (rilpivirine) Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended Drugs that are strong inducers of UGT1A1 or UGT1A9 are expected to decrease the plasma concentrations of cabotegravir. Drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes USE IN SPECIFIC POPULATIONS Pregnancy: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Discuss the benefit-risk of using CABENUVA during pregnancy and conception and consider that cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA. An Antiretroviral Pregnancy Registry has been established Lactation: Potential risks of breastfeeding include HIV-1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in a breastfed infant For more information, please see full US Prescribing Information for Cabenuva: APRETUDE (cabotegravir) extended-release injectable suspensions INDICATION APRETUDE is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test prior to initiating APRETUDE (with or without an oral lead-in with oral cabotegravir) for HIV-1 PrEP. IMPORTANT SAFETY INFORMATION BOXED WARNING: RISK OF DRUG RESISTANCE WITH USE OF APRETUDE FOR HIV-1 PRE-EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED HIV-1 INFECTION Individuals must be tested for HIV-1 infection prior to initiating APRETUDE or oral cabotegravir, and with each subsequent injection of APRETUDE, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Drug-resistant HIV-1 variants have been identified with use of APRETUDE by individuals with undiagnosed HIV-1 infection. Do not initiate APRETUDE for HIV-1 PrEP unless negative infection status is confirmed. Individuals who become infected with HIV-1 while receiving APRETUDE for PrEP must transition to a complete HIV-1 treatment regimen. CONTRAINDICATIONS Do not use APRETUDE in individuals: with unknown or positive HIV-1 status with previous hypersensitivity reaction to cabotegravir receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, and rifapentine WARNINGS AND PRECAUTIONS Comprehensive Management to Reduce the Risk of HIV-1 Infection: Use APRETUDE as part of a comprehensive prevention strategy, including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). APRETUDE is not always effective in preventing HIV-1 acquisition. Risk for HIV-1 acquisition includes, but is not limited to, condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network. Inform, counsel, and support individuals on the use of other prevention measures (e.g., consistent and correct condom use; knowledge of partner[s] HIV-1 status, including viral suppression status; regular testing for STIs) Use APRETUDE only in individuals confirmed to be HIV-1 negative. HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV-1 infection who are taking only APRETUDE, because APRETUDE alone does not constitute a complete regimen for HIV-1 treatment. Prior to initiating APRETUDE, ask seronegative individuals about recent (in past month) potential exposure events and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash). If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute HIV-1 infection When using APRETUDE, HIV-1 testing should be repeated prior to each injection and upon diagnosis of any other STIs Additional HIV testing to determine HIV status is needed if an HIV-1 test indicates possible HIV-1 infection or if symptoms consistent with acute HIV-1 infection develop following an exposure event. If HIV-1 infection is confirmed, then transition the individual to a complete HIV-1 treatment Counsel HIV-1 uninfected individuals to strictly adhere to the recommended dosing and testing schedule for APRETUDE Potential Risk of Resistance with APRETUDE: There is a potential risk of developing resistance to APRETUDE if an individual acquires HIV-1 either before, while taking, or following discontinuation of APRETUDE. To minimize this risk, it is essential to clinically reassess individuals for risk of HIV-1 acquisition and to test before each injection to confirm HIV-1–negative status. Individuals who are confirmed to have HIV-1 infection must transition to a complete HIV-1 treatment. If individuals at continuing risk of HIV-1 acquisition discontinue APRETUDE, alternative forms of PrEP should be considered and initiated within 2 months of the final injection of APRETUDE Long-Acting Properties and Potential Associated Risks with APRETUDE: Residual concentrations of cabotegravir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer). Take the prolonged-release characteristics of cabotegravir into consideration and carefully select individuals who agree to the required every-2-month injection dosing schedule because non-adherence or missed doses could lead to HIV-1 acquisition and development of resistance Hypersensitivity Reactions: Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with APRETUDE Discontinue APRETUDE immediately if signs or symptoms of hypersensitivity reactions develop. Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated Hepatotoxicity: Hepatotoxicity has been reported in a limited number of individuals receiving cabotegravir with or without known pre-existing hepatic disease or identifiable risk factors Clinical and laboratory monitoring should be considered and APRETUDE should be discontinued if hepatotoxicity is suspected and individuals managed as clinically indicated Depressive Disorders: Depressive disorders (including depression, depressed mood, major depression, persistent depressive disorder, suicidal ideation or attempt) have been reported with APRETUDE Promptly evaluate patients with depressive symptoms Risk of Reduced Drug Concentration of APRETUDE Due to Drug Interactions: The concomitant use of APRETUDE and other drugs may result in reduced drug concentration of APRETUDE Refer to the full Prescribing Information for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during use of, and after discontinuation of APRETUDE; review concomitant medications during use of APRETUDE ADVERSE REACTIONS The most common adverse reactions (incidence ≥1%, all grades) with APRETUDE were injection site reactions, diarrhea, headache, pyrexia, fatigue, sleep disorders, nausea, dizziness, flatulence, abdominal pain, vomiting, myalgia, rash, decreased appetite, somnolence, back pain, and upper respiratory tract infection. DRUG INTERACTIONS Refer to the full Prescribing Information for important drug interactions with APRETUDE Drugs that induce UGT1A1 may significantly decrease the plasma concentrations of cabotegravir USE IN SPECIFIC POPULATIONS Lactation: Assess the benefit-risk of using APRETUDE to the infant while breastfeeding due to the potential for adverse reactions and residual concentrations in the systemic circulation for up to 12 months or longer after discontinuation Pediatrics: Not recommended in individuals weighing less than 35 kg For more information, please see full US Prescribing Information for APRETUDE: RUKOBIA (fostemsavir) extended-release tablets INDICATION RUKOBIA, in combination with other antiretrovirals (ARVs), is indicated to treat HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current ARV regimen due to resistance, intolerance, or safety considerations. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA. Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John’s wort (Hypericum perforatum). WARNINGS AND PRECAUTIONS Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of RUKOBIA. QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 mg twice daily has been shown to significantly prolong the QTc interval of the electrocardiogram. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or in patients with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible to drug-induced QT interval prolongation. Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection: Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting RUKOBIA in patients co-infected with hepatitis B. Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of RUKOBIA and other drugs may occur (see Contraindications and Drug Interactions). Adverse reactions The most common adverse reaction (all grades, randomized cohort) observed in ≥5% of subjects was nausea (10%). 81% of adverse reactions reported with RUKOBIA were mild or moderate in severity. Drug interactions See the full Prescribing Information for RUKOBIA for a complete list of significant drug interactions. Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen if possible. Use the lowest possible starting dose for statins and monitor for statin-associated adverse events. Patients receiving RUKOBIA should not take doses of estrogen-based therapies, including oral contraceptives, that contain more than 30 mcg/day of ethinyl estradiol. Caution is advised particularly in patients with additional risk factors for thromboembolic events. Use in specific populations Pregnancy: There are insufficient human data on the use of RUKOBIA during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established. Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance, and adverse reactions in a breastfed infant. For more information, please see full US Prescribing Information for RUKOBIA: About ViiV Healthcare ViiV Healthcare is a global specialist HIV company established in November 2009 by GSK (LSE: GSK) and Pfizer (NYSE: PFE) dedicated to delivering advances in treatment and care for people living with HIV and for people who are at risk of acquiring HIV. Shionogi became a ViiV shareholder in October 2012. The company’s aims are to take a deeper and broader interest in HIV and AIDS than any company has done before and take a new approach to deliver effective and innovative medicines for HIV treatment and prevention, as well as support communities affected by HIV. For more information on the company, its management, portfolio, pipeline, and commitment, please visit viivhealthcare.com. About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com. Cautionary statement regarding forward-looking statements GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D “Risk factors” in the company's Annual Report on Form 20-F for 2022, and Q4 Results for 2023. Registered in England & Wales: GSK plc ViiV No. 3888792 Healthcare Limited No. 06876960 Registered Office: GSK plc 980 Great West Road Brentford, Middlesex United Kingdom TW8 9GS ViiV Healthcare Limited GSK Medicines Research Centre Gunnels Wood Road, Stevenage United Kingdom SG1 2NY References 1 Han, et al. Phase I Study of Cabotegravir Long-Acting Injectable Formulations Supports ≥4-Monthly Dose Interval. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 2 Leone, et al. VH3810109 (N6LS) in Antiretroviral Therapy–Naive Adults With HIV-1: Phase IIa BANNER Efficacy Data. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 3 Win, et al. High-Dose VH3810109 (N6LS) ± Recombinant Human Hyaluronidase PH20: Phase I SPAN Study Safety Results. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 4 Taiwo, et al. Safety and Efficacy of VRC07-523LS plus Long-Acting Cabotegravir in the Phase 2 ACTG A5357 Trial. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 5 Rana, et al. Long-acting Injectable CAB/RPV is Superior to Oral ART in PWH with adherence challenges: ACTG A5359. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 6 Kamya, et al. SEARCH Randomized trial of Dynamic Choice HIV Prevention including injectable cabotegravir (CAB-LA). Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 7 Hsu, et al. Real-World Effectiveness of Cabotegravir + Rilpivirine vs. Standard of Care Oral Regimens in the US. Presented at 31 Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 8 Sörstedt, et al. Switching to DTG+3TC vs 3-drug regimens in routine clinical care: long-term Swedish data. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 9 Data on File

Phase 2Phase 1Clinical ResultPhase 3

09 Mar 2023

·www.biospace.com

Fulcrum Therapeutics Announces Recent Business Highlights and Financial Results for the Fourth Quarter and Full Year 2022

― Company is working to address clinical hold on the Investigational New Drug application for FTX-6058 for the potential treatment of sickle cell disease ― ― FTX-6058 data from 12 mg cohort of Phase 1b trial show clinically relevant fetal hemoglobin increases of up to 10.0% ― ― On track to complete enrollment in Phase 3 REACH trial of losmapimod in facioscapulohumeral muscular dystrophy during 2H’23 ― ― In 1Q’23 completed public offering, generating approximately $117.3 million in net proceeds; Cash runway guidance into mid-2025 ― ― Company announces departure of Chief Medical Officer Santiago Arroyo, MD, Ph.D.; Appoints Iain Fraser, MBChB, D.Phil, as Interim Chief Medical Officer ― ― Conference call and webcast scheduled for 8:00 a.m. ET today ― CAMBRIDGE, Mass., March 09, 2023 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc.® (the “Company”) (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases, today reported financial results for the fourth quarter and full year 2022 and provided a business update, including on FTX-6058. “We are confident that FTX-6058 has the potential to provide a differentiated therapeutic option for people living with sickle cell disease and that the clinical and preclinical data generated to date demonstrate a favorable benefit-risk profile. We are working diligently to address the clinical hold,” said Robert J. Gould, Ph.D., Fulcrum’s interim president and chief executive officer. “Additionally, we remain on track to complete enrollment in the losmapimod Phase 3 REACH trial in the second half of 2023, and are excited about potentially being first to market with a treatment for FSHD patients who have no approved therapies.” Key Business Updates FTX-6058 On February 23, 2023, the FDA placed the investigational new drug (IND) application for FTX-6058 for the potential treatment of sickle cell disease (SCD) on full clinical hold. In its communication, the Agency noted preclinical data previously submitted in April, October and December 2022, and non-clinical and clinical evidence of hematological malignancies observed with other inhibitors of polycomb repressive complex 2 (PRC2). The Company received a formal Clinical Hold Letter from the Agency on February 24, 2023. Enrollment has been paused and dosing suspended in the Phase 1b trial of FTX-6058. The clinical hold noted that the pro hematological malignancies observed in the non-clinical studies of FTX-6058 is similar to that observed with other inhibitors of PRC2, and that hematological malignancies have been reported clinically with other PRC2 inhibitors. The Agency requested that Fulcrum further define the population where the potential benefit of continued treatment with FTX-6058 outweighs potential risk. Preceding the FDA hold: The Company made submissions to the FDA in April, October and December 2022 that included non-clinical data. In December, the FDA granted FTX-6058 Fast Track Designation for the treatment of SCD. The Company previously disclosed Phase 1b data from Cohort 1 subjects in the 6 mg cohort (n=10): Primary endpoint showed up to 9.5% absolute fetal hemoglobin (HbF) increases from baseline, data suggest no difference in response in subjects on (n=3) and off (n=7) background hydroxyurea. FTX-6058 treatment appears to result in dose dependent and clinically relevant increases in HbF; all subjects adherent to the dosing regimen showed a response. Improved biomarkers of hemolysis were observed in evaluable patients. FTX-6058 was generally well tolerated with no drug-related treatment emergent serious adverse events and no discontinuations due to treatment emergent adverse events to date. Data from subjects in the 2 mg cohort (n=2) demonstrated continued absolute HbF increases up to 4.6% through the end of treatment, suggesting 2 mg is a potentially minimally efficacious dose. Data from a subject in the 12 mg dose cohort (n=3), prior to the suspension of the trial, showed up to 10.0% absolute HbF increases from baseline after 42 days of treatment. On February 17, 2023, the Company responded to a request received on February 9, 2023, from the FDA about non-clinical data submitted in 2022. The Company is confident in its ability to address the Agency’s feedback and looks forward to providing further updates as the process unfolds. Losmapimod Enrollment is ongoing in the REACH Phase 3 pivotal trial evaluating losmapimod in FSHD at sites in the United States, Canada and Europe. On track to complete enrollment in the second half of 2023. In October 2022, the Company presented new data from the open label extension portion of the Phase 2 ReDUX4 study of losmapimod for the treatment of FSHD. Corporate Updates Completed underwritten public offering of common stock in January 2023, raising approximately $117.3 million in net proceeds. Santiago Arroyo, MD, Ph.D., recently resigned from the Company, effective March 7, 2022, to pursue another opportunity. Iain Fraser, MBChB, D.Phil was appointed Interim Chief Medical Officer (CMO), effective March 9, 2023. Dr. Fraser brings over two decades of experience advancing therapies through early- and late-stage development and possesses deep expertise in regulatory affairs. He most recently served as Vice President and Clinical Fellow at AlloVir, an Elevate Bio Company. He previously held clinical development roles of increasing responsibility at Abide Therapeutics (acquired by Lundbeck in 2019) and Merck, where he led the first-in-human clinical trials of a range of compounds across therapeutic areas, and contributed to the development of Zepatier®, Zinplava™ and Recarbrio™, as well as the pediatric development of Januvia® and Maxalt®. He received a Master of Science in Clinical Investigation from Harvard University and a Doctor of Philosophy in Experimental Pathology from the University of Oxford. Dr. Fraser received his Bachelor of Science in Biochemistry as well as his Bachelor of Medicine, Bachelor of Surgery – MBChB from the University of Cape Town. Alan Ezekowitz, MBChB, D.Phil, member of the Fulcrum Board of Directors since February 2017, will serve as a senior clinical advisor to provide program continuity. Fourth Quarter and Full Year 2022 Financial Results Cash Position: As of December 31, 2022, cash, cash equivalents and marketable securities were $202.9 million as compared to $218.2 million as of December 31, 2021. The decrease in cash is primarily due to our net cash used in operating activities during 2022, partially offset by proceeds from our equity offering in August 2022. Collaboration Revenue: Collaboration revenue was $0.7 million for the fourth quarter of 2022 as compared to $5.1 million for the fourth quarter of 2021. The decrease of $4.4 million was primarily due to the winding down of Fulcrum's collaboration agreement with Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc. Collaboration revenue was $6.3 million for the year ended December 31, 2022, as compared to $19.2 million for the year ended December 31, 2021. The decrease of $12.9 million was primarily due to the winding down of Fulcrum's collaboration agreement with Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc. Operating Expenses: Total operating expenses were $28.7 million for the fourth quarter of 2022 as compared to $28.6 million for the fourth quarter of 2021. An increase of $0.4 million in G&A expenses was primarily due to increased employee-related costs, including increased stock-based compensation expense. A decrease of $0.3 million in R&D expenses was primarily due to a decrease in employee-related costs, including increased stock-based compensation expense, partially offset by increased external research and development costs to support our lead programs. Total operating expenses were $118.9 million for the year ended December 31, 2022, as compared to $100.2 million for the year ended December 31, 2021. An increase of $7.1 million in R&D expenses was primarily due to increased external research and development costs to support our lead programs, including a $5.0 million milestone paid to GlaxoSmithKline plc, upon the initiation of the Phase 3 REACH trial under our right of reference and license agreement. An increase of $11.2 million in G&A expenses was primarily due to increased employee-related costs, including increased stock-based compensation expense, increased professional services costs and increased facility-related costs. Net Loss: Net loss was $26.1 million for the fourth quarter of 2022, as compared to a net loss of $23.5 million for the fourth quarter of 2021. Net loss was $109.9 million for the year ended December 31, 2022, as compared to a net loss of $80.8 million for the year ended December 31, 2021. Financial Guidance Fulcrum expects that its existing cash, cash equivalents, and marketable securities will be sufficient to fund its operating expenses and capital expenditure requirements into mid-2025. Conference Call and Webcast Fulcrum Therapeutics, Inc. will host a conference call and webcast today at 8:00 a.m. ET to review the fourth quarter and full year 2022 recent business highlights and financial results. Individuals may participate in the live call via telephone by dialing (877) 407-0792 (domestic) or (201) 689-8263 (international) and using the conference ID: 13735955. Participants are asked to dial in 15 minutes before the start of the call to register. The webcast will be accessible through the Investor Relations section of Fulcrum’s website at or by clicking here. Following the live webcast, an archived replay will also be available for 90 days. About Fulcrum Therapeutics Fulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases in areas of high unmet medical need. Fulcrum’s two lead programs in clinical development are losmapimod, a small molecule for the treatment of facioscapulohumeral muscular dystrophy (FSHD), and FTX-6058, a small molecule designed to increase expression of fetal hemoglobin for the treatment of sickle cell disease (SCD) and other hemoglobinopathies, including beta-thalassemia. Fulcrum’s proprietary product engine, FulcrumSeek™, identifies drug targets that can modulate gene expression to treat the known root cause of gene mis-expression. For more information, visit and follow us on Twitter @FulcrumTx and LinkedIn. About FTX-6058 FTX-6058 is an investigational oral small-molecule inhibitor of Embryonic Ectoderm Development (EED) that was discovered using FulcrumSeek™, Fulcrum’s proprietary discovery engine. Inhibition of EED leads to potent downregulation of key fetal globin repressors, including BCL11A, thereby causing an increase in fetal hemoglobin (HbF). FTX-6058 is being developed for the treatment of sickle cell disease (SCD) and other hemoglobinopathies. Initial data in SCD demonstrated proof-of-concept and achieved absolute levels of HbF increases associated with potential overall patient benefit. To date, FTX-6058 has been generally well-tolerated in people with SCD with up to three months of exposure, with no serious treatment-emergent adverse events reported. FTX-6058 has been granted U.S. Food and Drug Administration (FDA) Fast Track designation and Orphan Drug Designation for the treatment of SCD. About Sickle Cell Disease Sickle cell disease (SCD) is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. This gene encodes a protein that is a key component of hemoglobin, a protein complex whose function is to transport oxygen in the body. The result of the mutation is less efficient oxygen transport and the formation of red blood cells that have a sickle shape. These sickle shaped cells are much less flexible than healthy cells and can block blood vessels or rupture cells. People with SCD typically suffer from serious clinical consequences, which may include anemia, pain, infections, stroke, heart disease, pulmonary hypertension, kidney failure, liver disease, and reduced life expectancy. About Losmapimod Losmapimod is a selective p38α/β mitogen activated protein kinase (MAPK) inhibitor. Fulcrum exclusively in-licensed losmapimod from GSK following Fulcrum’s discovery of the role of p38α/β inhibitors in the reduction of DUX4 expression and an extensive review of known compounds. Results reported from the Phase 2b ReDUX4 trial demonstrated slowed disease progression and improved function, including positive impacts on upper extremity strength and functional measures supporting losmapimod’s potential to be a transformative therapy for the treatment of FSHD. Although losmapimod had never previously been explored in muscular dystrophies, it had been evaluated in more than 3,600 subjects in clinical trials across multiple other indications, with no safety signals attributed to losmapimod. Losmapimod has been granted U.S. Food and Drug Administration (FDA) Fast Track designation and Orphan Drug Designation for the treatment of FSHD. Losmapimod is currently being evaluated in a Phase 3 multi-center randomized, double-blind, placebo-controlled, 48-week parallel-group study in people with FSHD (NCT05397470). About FSHD FSHD is a serious, rare, progressive and debilitating disease for which there are no approved treatments. It is characterized by fat infiltration of skeletal muscle leading to muscular atrophy involving primarily the face, scapula and shoulders, upper arms, and abdomen. Impact on patients includes profound decreases in the ability to perform activities of daily living, loss of upper limb function, loss of mobility and independence and chronic pain. FSHD is one of the most common forms of muscular dystrophy and has an estimated patient population of 16,000 to 38,000 in the United States alone. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release are forward-looking statements, including express or implied statements regarding the clinical hold on FTX-6058, including Fulcrum’s ability to resolve such hold; enrollment in Fulcrum’s ongoing clinical trial of losmapimod and timing of completion; potential therapeutic benefit of FTX-6058 and losmapimod; Fulcrum’s ability to market a treatment for FSHD patients; and Fulcrum’s cash runway, among others. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with resolving the clinical hold on FTX-6058 and responding to FDA’s requests; Fulcrum’s ability to continue to advance its product candidates in clinical trials; initiate and enroll clinical trials on the timeline expected or at all; obtain and maintain necessary approvals from the FDA and other regulatory authorities; replicate in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials of losmapimod, FTX-6058 (if resumed) and any other product candidates; obtain, maintain or protect intellectual property rights related to its product candidates; manage expenses; realize the anticipated benefits of the strategic realignment; manage executive and employee turnover; and raise the substantial additional capital needed to achieve its business objectives, among others. For a discussion of other risks and uncertainties, and other important factors, any of which could cause Fulcrum’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties, and other important factors, in Fulcrum’s most recent filings with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent Fulcrum’s views as of the date hereof and should not be relied upon as representing Fulcrum’s views as of any date subsequent to the date hereof. Fulcrum anticipates that subsequent events and developments will cause Fulcrum’s views to change. However, while Fulcrum may elect to update these forward-looking statements at some point in the future, Fulcrum specifically disclaims any obligation to do so. Fulcrum Therapeutics, Inc. Selected Consolidated Balance Sheet Data (In thousands) (Unaudited) December 31, 2022 December 31, 2021 Cash, cash equivalents, and marketable securities $ 202,921 $ 218,162 Working capital(1) 190,794 206,799 Total assets 226,685 235,000 Total stockholders’ equity 198,942 211,539 (1) Fulcrum defines working capital as current assets minus current liabilities. Fulcrum Therapeutics, Inc. Consolidated Statements of Operations (In thousands, except per share data) (Unaudited) Three Months Ended December 31, Year Ended December 31, 2022 2021 2022 2021 Collaboration revenue $ 685 $ 5,058 $ 6,342 $ 19,163 Operating expenses: Research and development 18,566 18,912 76,782 69,701 General and administrative 10,130 9,705 41,694 30,516 Restructuring expenses (38 ) — 427 — Total operating expenses 28,658 28,617 118,903 100,217 Loss from operations (27,973 ) (23,559 ) (112,561 ) (81,054 ) Other income, net 1,838 75 2,690 207 Net loss $ (26,135 ) $ (23,484 ) $ (109,871 ) $ (80,847 ) Net loss per share, basic and diluted $ (0.50 ) $ (0.58 ) $ (2.44 ) $ (2.29 ) Weighted-average common shares outstanding, basic and diluted 52,077 40,579 44,991 35,361 Contact: Investors: Chris Calabrese LifeSci Advisors, LLC ccalabrese@lifesciadvisors.com 917-680-5608 Media: Dee Smith Executive Director, Corporate Communications Fulcrum Therapeutics, Inc. dsmith@fulcrumtx.com 202-746-1324

Phase 2Phase 1Clinical ResultFast TrackFinancial Statement

100 Deals associated with Elbasvir/Grazoprevir

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KEGG	Wiki	ATC	Drug Bank
-	Elbasvir/Grazoprevir	J05AP54	-

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Hepatitis C	CN	Merck Sharp & Dohme BV	28 Apr 2018
Hepatitis C, Chronic	CA	Merck Canada, Inc.	19 Jan 2016

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	Phase 3	-	Merck Sharp & Dohme Corp.	01 Sep 2019
Chronic hepatitis C genotype 1b	Phase 3	KZ	Merck Sharp & Dohme Corp.	01 Oct 2017
Fibrosis, Liver	Phase 3	KZ	Merck Sharp & Dohme Corp.	01 Oct 2017
HIV Infections	Phase 3	-	Merck Sharp & Dohme Corp.	22 Oct 2014
Fibrosis	Phase 3	-	Merck Sharp & Dohme LLC	09 May 2014
Chronic Kidney Diseases	Phase 3	-	Merck Sharp & Dohme Corp.	17 Mar 2014
Acute hepatitis	Phase 2	FR	Merck Sharp & Dohme Corp.	31 May 2017
Heart Failure	Phase 2	US	Merck Sharp & Dohme Corp.	16 May 2017
Kidney Failure, Chronic	Phase 2	US	Merck Sharp & Dohme Corp.	01 May 2016
Chronic hepatitis C genotype 2	Phase 2	-	Merck Sharp & Dohme Corp.	28 Nov 2011

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02743897 (THINKER, CTgov)	Phase 1/2	Kidney Failure, Chronic \| Hepatitis C	62	Mavyret+Zepatier	kdzmomjjwp(zqijidluyh) = ipyopxbdhn xjqwvhaxyx (qegmtpedww, otokdotmop - gnumasykfx) View more	-	15 Jun 2023
NCT03823911 (CHROME, CTgov)	Phase 4	Cardiovascular Diseases \| HIV Infections \| Hepatitis C	87	Cardiac MRI+Elbasvir / Grazoprevir Oral Tablet [Zepatier] (Hepatitis C Mono-Infected)	ipvmizirhg(eipbbizgba) = fsicaqpoff ceffiykdfx (gjhtmmozqv, dmpcvysmaj - hlqarqrtpc) View more	-	22 May 2023
NCT03823911 (CHROME, CTgov)	Phase 4	Cardiovascular Diseases \| HIV Infections \| Hepatitis C	87	Cardiac MRI+Elbasvir / Grazoprevir Oral Tablet [Zepatier] (HIV and Hepatitis C Co-Infected)	ipvmizirhg(eipbbizgba) = dkeuziybon ceffiykdfx (gjhtmmozqv, ofkfmytncy - gerczhwypm) View more	-	22 May 2023
NCT03724149 (SHELTER, CTgov)	Phase 1/2	Hepatitis C	10	Epclusa+Zepatier	qqotfoexcw(ggzciqxyfz) = gdxdmxnmgz dgherfqyym (cmqqmsrggh, owbzezgypv - bwmyouehyp) View more	-	14 Apr 2023
NCT02902120 (CTgov)	Phase 4	Hepatitis C, Chronic \| Chronic Kidney Diseases	21	Post-transplant Grazoprevir+Elbasvir	wcznevlnrg(gnhjhdjytx) = hvtplyaocf jczjpecrpe (vsonapccgo, yavmeibzfl - hwytfyzvjk) View more	-	18 Nov 2022
NCT03578640 (ELEGANT-4, DDW2022)	Phase 3	Hepatitis C	30	Elbasvir/Grazoprevir	uepkivrgnc(litmxiareu) = dqijfzxwkc talparodmp (rrcgzocldl, 90 - 100) View more	Positive	21 May 2022
NCT03578640 (ELEGANT-4, Pubmed)	Phase 3	Hepatitis C	30	Elbasvir/Grazoprevir fixed-dose combination	lpxnaicezo(rhkvxmsbqr) = uukfbvzdyh riqhgernvy (rgguvalbyk, 90 - 100) View more	Positive	09 Feb 2022
NCT03365635 (HD, CTgov)	Phase 4	Cross Infection \| Hepatitis C	6	Elbasvir 50 MG / Grazoprevir 100 MG [Zepatier] (Genotype 1a -Rx Naive -no NS5A Polymorph)	pnwirisgdl(ooqbklluqo) = nvwsgcostp kobxeevhvu (hmosunlbkf, dhuiuaptlz - cjpgrvbgww) View more	-	15 Dec 2021
NCT03365635 (HD, CTgov)	Phase 4	Cross Infection \| Hepatitis C	6	Elbasvir 50 MG / Grazoprevir 100 MG [Zepatier] (Genotype 1a, Rx Naive + NS5A Polymorph)	pnwirisgdl(ooqbklluqo) = kyycknlgio kobxeevhvu (hmosunlbkf, yzhmklxnxm - fvltipcdrq) View more	-	15 Dec 2021
NCT03723824 (Pubmed)	Phase 4	Chronic hepatitis C genotype 1b	14	Grazoprevir 100mg/Elbasvir 50mg	eaziaibkld(jjuyfyihng) = ornjxyvyyq poomomlafw (jqnzdoyrgz )	Positive	13 Dec 2021
NCT03236506 (ADVANCE \| ADVANCE HCV, CTgov)	Phase 2	Hepatitis C	129	Sofosbuvir 400 MG+Elbasvir/Grazoprevir 50 MG-100 MG Oral Tablet (Daily Observed Therapy)	ojpeawzsae(btqirygikq): Odds Ratio (OR) = 0.64 (95% CI, 0.14 - 3.00), P-Value = 0.67	-	18 Nov 2021
NCT03236506 (ADVANCE \| ADVANCE HCV, CTgov)	Phase 2	Hepatitis C	129	Sofosbuvir 400 MG+Elbasvir/Grazoprevir 50 MG-100 MG Oral Tablet (Fortnightly Pick-up)		-	18 Nov 2021
NCT02251990 (5172-067 \| C-CORAL, Pubmed)	Phase 3	Hepatitis C	152	Elbasvir/Grazoprevir 50mg/100mg	yudpealcig(pdvypzkkxp) = psdnedrxdk fzybhzxxxn (plngdysuli )	Positive	01 Dec 2020

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