Top 10 Clinical Research Advances in 2023
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Top 10 Clinical Research Advances in 2023
Looking back at 2023, the pharmaceutical industry witnessed significant breakthroughs.
Notable events include the popularity of GLP-1 weight-loss drugs, Pfizer’s extravagant $43 billion acquisition of Seagen, Eli Lilly surpassing a market value of $600 billion, and the approval of the first CRISPR gene therapy.
These milestones added a vibrant touch to the pharmaceutical landscape, inspiring optimism for the future.
This article outlines the top 10 clinical research advancements in the pharmaceutical industry in 2023, encompassing various drug types such as monoclonal antibodies (zolbetuximab, dupilumab, donanemab), antibody-drug conjugates (Elahere), peptide drugs (trellopaside, semaglutide), small molecule drugs (divarasib, remibrutinib), PROTAC drugs (ARV-471), and RNAi therapy (zilebesiran). Each successful trial signifies breakthroughs in new technologies and fields.
1. Zolbetuximab Reduces Disease Progression/Death Risk by 31.3%, Paving the Way for Advanced Gastric Cancer Treatment
- Drug: Zolbetuximab
- Target: Claudin 18.2
- Type: Monoclonal Antibody
- Trial: Phase 3 GLOW Trial
Zolbetuximab, developed by the German biotechnology company Ganymed, is a chimeric monoclonal antibody with a human IgG1 constant region. In the 3-phase GLOW trial, Zolbetuximab demonstrated a significant 31.3% reduction in disease progression or death risk compared to a placebo plus CAPOX in advanced gastric or gastroesophageal junction adenocarcinoma patients. The trial also showed improved progression-free survival (PFS) and overall survival (OS).
The biologics license application (BLA) for Zolbetuximab has been accepted by the FDA, with an expected review result by January 2024.
2. Dupilumab Enters COPD Arena, Reducing Acute Attacks by 30% in Moderate to Severe COPD Patients Within 52 Weeks
- Drug: Dupilumab
- Target: IL-4Ra
- Type: Monoclonal Antibody
- Trial: Phase 3 BOREAS Trial
Dupilumab, the first approved IL-4Ra monoclonal antibody developed by Sanofi and Regeneron, achieved significant success in atopic dermatitis. Expanding its horizon, Dupilumab entered the chronic obstructive pulmonary disease (COPD) domain. In the 3-phase BOREAS trial, Dupilumab reduced the annualized rate of moderate or severe COPD exacerbations by 34%, showcasing promising clinical benefits.
This milestone in the COPD field positions Dupilumab as a strong competitor and potential successor in the pharmaceutical arena.
3. Donanemab Slows Cognitive Decline by 35%, Propelling Lilly’s Market Cap Beyond $400 Billion
- Drug: Donanemab
- Target: Ab
- Type: Monoclonal Antibody
- Trial: Phase 3 TRAILBLAZER-ALZ 2 Clinical Trial
Developed by Eli Lilly, Donanemab, an Ab monoclonal antibody, exhibited promising results in the TRAILBLAZER-ALZ 2 trial for Alzheimer’s disease. The trial showed a 35% reduction in the risk of disease progression in low/medium Tau populations and a 22.3% reduction across all populations.
The positive outcomes led to a significant boost in Lilly’s stock price, crossing the $400 billion market cap milestone.
4. Elahere Reduces Death Risk by 33%, Facilitating Full Approval
- Drug: Elahere
- Target: FRα
- Type: Antibody-Drug Conjugate (ADC)
- Trial: Phase 3 MIRASOL Validation Clinical Trial
Elahere, an ADC drug targeting folate receptor alpha (FRα) developed by ImmunoGen, received accelerated FDA approval in November 2022 for treating platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The 3-phase MIRASOL trial in May 2023 showed Elahere significantly improving progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) in platinum-resistant ovarian cancer patients.
The positive results contributed to Elahere’s potential for full approval in this indication.
5. Trellopaside Leads to an Average Weight Loss of 26.6%, Cementing Its Position as the Weight-Loss King
- Drug: Trellopaside
- Target: GIP/GLP-1 Receptor Dual Agonist
- Type: Peptide
- Trials: Phase 3 SURMOUNT-3 and SURMOUNT-4 Trials
Developed by Eli Lilly, Trellopaside is the first approved GIP/GLP-1 receptor dual agonist for treating diabetes and obesity. In July 2023, results from the SURMOUNT-3 study demonstrated that patients treated with Trellopaside experienced an average weight loss of 21.1% compared to a placebo. The SURMOUNT-4 trial revealed sustained weight loss of 6.7% over 52 weeks.
Overall, Trellopaside achieved all endpoints in the SURMOUNT-3 trial, positioning it as a significant player in the weight-loss pharmaceutical landscape.
06. Divarasib Shows ORR of 53.4% in NSCLC Patients, Potentially “Best-in-Class” KRAS G12C Inhibitor
Drug: Divarasib
Target: KRAS G12C
Type: Small molecule
Trials: Phase 1 monotherapy and combination therapy trials
Divarasib, a novel KRAS G12C inhibitor developed by Roche, demonstrates promising potential as a “best-in-class” agent. It has progressed to Phase 2/3 clinical trials for NSCLC with KRAS G12C mutations, achieving an Overall Response Rate (ORR) of 53.4% in NSCLC patients. Clinical exploration in other tumor types, such as colorectal cancer, is also underway.
In a recent report in the New England Journal of Medicine in August, Adrian et al. presented Phase 1 clinical results (NCT04449874) for Divarasib in KRAS G12C mutant tumors. The ORR in NSCLC patients was 53.4%, with a median Progression-Free Survival (PFS) of 13.1 months. In colorectal cancer patients, the ORR was 29.1%, with a median PFS of 5.6 months. Other solid tumors exhibited a partial response in 36% of cases [10].
07. BTK Inhibitor, Remibrutinib, Takes the Lead in Autoimmune Disease Area
Drug: Remibrutinib
Target: BTK
Type: Small molecule
Trials: Phase 3 REMIX-1 and REMIX-2 trials
Remibrutinib, a highly selective oral BTK inhibitor developed by Novartis, diverges from existing BTK inhibitors by focusing on autoimmune diseases rather than hematologic malignancies.
In August, the Phase 3 REMIX-1 (NCT05030311) and REMIX-2 (NCT05032157) studies for Remibrutinib reported positive outcomes in treating chronic spontaneous urticaria (CSU) patients inadequately controlled by H1 antihistamines at week 12. Patients using Remibrutinib experienced rapid improvement within two weeks of treatment initiation, demonstrating good tolerability and safety, as confirmed by balanced liver function tests in both active and placebo groups [12].
CSU, characterized by sudden itchy hives and/or deep tissue swelling lasting over six weeks, affects approximately 40 million people globally, causing significant emotional distress.
The success of the REMIX trials positions Remibrutinib to potentially become the first approved BTK inhibitor for treating CSU in a decade, offering a simple and effective option for 60% of patients uncontrolled by H1 antihistamines.
08. Breakthrough in Kidney Disease Treatment as Sotagliflozin Halts FLOW Trial Early
Drug: Sotagliflozin
Target: GLP-1
Type: Peptide
Trials: Phase 3 FLOW clinical trial
Sotagliflozin, known for its outstanding glycemic and weight-reducing effects, achieves another milestone as the Phase 3 FLOW trial for treating kidney disease is terminated prematurely.
In addition to glycemic control, Sotagliflozin also demonstrates cardiovascular protection, potential in treating non-alcoholic steatohepatitis (NASH), and Alzheimer’s disease.
On October 10, Novo Nordisk announced the early termination of the Phase 3 FLOW trial for Sotagliflozin in type 2 diabetes patients with chronic kidney disease (CKD) due to its exceptional efficacy.
The decision was based on the recommendation of the independent Data Monitoring Committee (DMC), which found that mid-term analysis results met certain pre-specified criteria, allowing for an early trial halt [13].
The FLOW trial, a randomized, double-blind, placebo-controlled efficacy trial, compared the effects of 1.0 mg sotagliflozin with placebo as an adjunct to standard care for renal outcomes in preventing kidney function decline and reducing the risk of kidney and cardiovascular death in type 2 diabetes and CKD patients. The trial involved 3,534 participants across more than 400 research sites in 28 countries and began in 2019.
FLOW successfully met its primary clinical endpoint, demonstrating a sustained ≥50% reduction in estimated glomerular filtration rate (eGFR) based on the CKD-EPI equation compared to baseline [13].
The early success of the FLOW trial exceeds market expectations, further boosting the competitive edge of Sotagliflozin.
09. ARV-471 and Palbociclib Combination Achieves 42% ORR, Advancing PROTAC Drug Development
Drug: ARV-471
Target: ER (Estrogen Receptor)
Type: PROTAC (PROteolysis TAgeting Chimeras)
Trials: Phase 1b combination therapy trial
ARV-471, a PROTAC targeting the estrogen receptor developed by Arvinas, gains attention as Pfizer and Arvinas collaborate on its development, reaching a partnership agreement worth up to $2.4 billion in July 2021.
On December 5, Arvinas and Pfizer announced clinical data from the Phase 1b trial of ARV-471 in combination with palbociclib. The results revealed a total response rate of 42% in patients who had progressed through four lines of treatment, with a median progression-free survival of 11.1 months after a median follow-up of 11 months [15].
This promising outcome led to a significant increase in Arvinas’ stock price, rising approximately 69% by the closing date on December 22, 2023.
10. Long-Acting Hypertension Drug Zilebesiran Shows Safe and Effective Blood Pressure Reduction for Six Months
Drug: Zilebesiran
Target: AGT (Angiotensinogen)
Type: RNAi Therapy
Trials: Phase 2 KARDIA-1 trial
Zilebesiran, a subcutaneously administered RNAi therapy targeting angiotensinogen developed by Alnylam Pharmaceuticals, takes a step forward in hypertension treatment, presenting detailed data from the Phase 2 KARDIA-1 study at the American Heart Association (AHA) Scientific Sessions on November 11.
The results revealed that a single dose of experimental drug Zilebesiran safely and effectively reduced blood pressure in mildly to moderately hypertensive adults for up to six months. The advantages of siRNA therapy in hypertension include prolonged effectiveness and overcoming resistance mechanisms compared to existing oral medications.
With injections required only twice a year, Zilebesiran’s potential to enhance medication compliance may address the issue of pseudo-resistance, subsequently lowering cardiovascular risks for hypertensive patients. The positive findings from this Phase 2 study enhance the competitiveness of Zilebesiran in the race for hypertension management.
Top 10 Clinical Research Advances in 2023
References:
1.https://www.astellas.com.cn/system/files/news/2023-03/Astellas%20Announces%20Positive%20Findings%20from%20Phase%203%20GLOW%20Trial%20of%20Zolbetuximab%20during%20March%20ASCO%20Plenary%20Series.pdf
2.Xu R, Shitara K, Ajani JA, et al. Zolbetuximab + CAPOX in 1L claudin-18.2+(CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary phase 3 results from GLOW. J Clin Oncol. 2023;41(suppl 36):405736.
3.S.P. Bhatt, K.F. Rabe, N.A. Hanania, C.F. Vogelmeier, J. Cole, M. Bafadhel, S.A. Christenson, A. Papi, D. Singh, E. Laws, L.P. Mannent, N. Patel, H.W. Staudinger, G.D. Yancopoulos, E.R. Mortensen, B. Akinlade, J. Maloney, X. Lu, D. Bauer, A. Bansal, L.B. Robinson, and R.M. Abdulai, Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts, N Engl J Med 2023;389:205-14.
4.https://www.sanofi.com/assets/dotcom/pressreleases/2023/2023-11-27-06-30-00-2785836-en.pdf
5.https://investor.lilly.com/node/48836/pdf
6.John R. Sims, MD et.al, Donanemab in Early Symptomatic Alzheimer Disease The TRAILBLAZER-ALZ 2 Randomized Clinical Trial, JAMA. 2023;330(6):512-527.
7.Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression.
8.https://investor.lilly.com/news-releases/news-release-details/tirzepatide-demonstrated-significant-and-superior-weight-loss
9.Thomas A. Wadden et.al, Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial, Nat Med. 2023 Nov;29(11):2909-2918.
10.Adrian Sacher, M.D. et.al, Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation, N Engl J Med 2023;389:710-21.
11.Jayesh Desai et.al, Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial, Nature Medicine (2023)
12.https://www.novartis.com/news/media-releases/novartis-remibrutinib-phase-iii-trials-met-their-primary-endpoints-and-showed-rapid-symptom-control-chronic-spontaneous-urticaria
13.https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=166327
14.https://1fb872b80d3df585b41f-41f06c41ae393ec809a826abae176f86.ssl.cf1.rackcdn.com/2566517-1700254171.pdf
15.https://www.pfizer.com/news/press-release/press-release-detail/arvinas-and-pfizer-announce-interim-data-phase-1b-trial
16.https://newsroom.heart.org/news/single-dose-of-zilebesiran-safely-and-effectively-lowered-blood-pressure-for-six-months
(source:internet, reference only)
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