Top 10 Drugs Expected to Receive FDA Approval in 2024: Profiles and Pipeline Highlights

Mar 09, 2024 06:30 CST Updated 06:30

Madrigal Pharmaceuticals

Developer of Fatty Liver Disease Treatment Drugs

Acceleron Pharma

Developer and Producer of Novel Biologic Therapeutics

Day One Biopharmaceuticals

Cancer Drug Developer

Daiichi-Sankyo

Pharmaceutical R&D Developer

Amgen

Developer of Treatment Drugs for Serious Diseases

Spark Therapeutics

Gene Therapy Developer

Alexion

Developer of New Drugs for Rare Disease Treatment

Roche

Oncology Drug Research, Development, and Manufacturing

Karuna Therapeutics

Developer of Treatment Drugs for Mental and Neurological Disorders

AstraZeneca

Biopharmaceutical Manufacturer

Source: PharmaBlock

Written by: May Edited by: Vitamin

From the beginning of 2024 to date, the FDA has approved Zelsuvmi for the treatment of infectious molluscum contagiosum in adults and children aged one year and above, as well as Lifileucel, the world's first solid tumor TIL therapy. What drugs are expected to be approved by the FDA from March to the end of the year?

Resmetirom

THR-β Selective Agonist

Resmetirom is a once-daily oral thyroid hormone receptor-beta (THR-β) selective agonist developed by Madrigal Pharmaceuticals for the treatment of non-alcoholic steatohepatitis (NASH).THR-β is responsible for regulating metabolic pathways in the liver,In NSAH patients, THR-B dysfunction leads to reduced thyroid hormone levels, causing liver function impairment.

Resmetirom was granted Breakthrough Therapy Designation by the FDA on April 18, 2023, for the treatment of NASH patients with liver fibrosis.

In June 2023, Stephen et al. reported the results of the MAESTRO-NAFLD-1 trial in Nature Medicine: The incidence of treatment-emergent adverse events (TEAE) with resmetirom was 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom), and 81.8% (placebo).Indicates that Resmetirom is safe and well-tolerated.

LDL-C was reduced by 11.1% and 12.6%, apoB was reduced by 15.6% and 18.0%, triglycerides were reduced by 15.4% and 20.4%, and liver fat was reduced by 34.9% and 38.6% at 16 weeks in the 80mg and 100mg resmetirom groups, respectively.^[1]。

MRI-PDFF (Magnetic Resonance Imaging-Proton Density Fat Fraction) measurements showed that the median CFB % of liver fat in the 80mg and 100mg resmetirom groups decreased by 40.8% and 47.7%, respectively, at 16 weeks, and by 42.5% and 48.2%, respectively, at 52 weeks (Figure 1).

Figure 1. MAESTRO-NAFLD-1 Trial Results

In July 2023, Madrigal completed the rolling submission of the New Drug Application (NDA) for Resmetirom to the FDA, and in September, Madrigal announcedFDA Accepts NDA for Resmetirom for the Treatment of Adults with NASH and Liver Fibrosis, Grants Priority Review under PDUFA(PDUFA) date is March 14, 2024.

On February 8, 2024, Harrison et al. reported the results of the Phase III MAESTRO-NASH trial in the New England Journal of Medicine: 25.9% of patients in the 80 mg resmetirom group and 29.9% of patients in the 100 mg resmetirom group achieved NASH resolution without fibrosis worsening, compared to 9.7% in the placebo group.In the 80mg resmetirom group, 24.2% of patients achieved at least one stage of fibrosis improvement.，NAFLD（Nonalcoholic Fatty Liver DiseaseActivityThe score did not worsen.100 mg rEsMetirom GroupAt 25.9%,Whereas the placebo group was 14.2% (Figure 2)^[2]。

Figure 2. Results of the MAESTRO-NASH Trial

Sotatercept

ACVR2A Fusion Protein

Sotatercept was originally developed by Acceleron Pharma.A Potential "First-in-class" Type IIA Activin Receptor (ACVR2A) Fusion ProteinIn September 2021, Merck acquired Acceleron Pharma for $11.5 billion, bringing sotatercept into its portfolio.

As early as April 2020, Acceleron Pharma received FDA Breakthrough Therapy Designation for the treatment of pulmonary arterial hypertension (PAH).Becomes the first PAH investigational therapy to receive Breakthrough Therapy designation.

On September 12, 2023, Merck announced the results of an exploratory post-hoc analysis of the Phase III STELLAR trial of sotatercept:Sotatercept can reduce the size of the right side of the heart, and improve right ventricular function and hemodynamic parameters after 24 weeks of treatment in patients with PAH.

On September 28, 2023, Merck & Co. announced that the FDA had accepted the Biologics License Application (BLA) for Sotatercept for priority review for the treatment of adult patients with PAH.FDA Sets PDUFA Date for March 26, 2024^[3,4]。

The priority review was based on data from the Phase III STELLAR trial, which included 323 adult participants. Baseline characteristics were similar across groups: 79.3% were female, with an average age of 47.9 ± 14.8 years; 48.6% were classified as World Health Organization (WHO) functional class (FC) II, and 51.4% as WHO FC III; 61.3% were receiving triple combination therapy, and 39.9% were undergoing parenteral prostanoid therapy.

The study results showed that: the Sotatercept group increased by 34.4 meters in the 6-minute walk distance (6MWD), while the placebo group increased by 1 meter.

Sotatercept demonstrated statistically significant and clinically meaningful improvements in 8 of the 9 secondary endpoint measures, including reductions in pulmonary vascular resistance (PVR), decreased levels of N-terminal pro-B-type natriuretic peptide, and improvement in WHO functional class.

In addition, the Phase III HYPERION study of Sotatercept in newly diagnosed intermediate- to high-risk PAH participants, as well as the Phase III ZENITH study in WHO functional class FC III or IV high-risk mortality participants, are currently ongoing.

Tovorafenib

Pan-RAF Kinase Inhibitor

Tovorafenib is an orally available, brain-penetrant pan-RAF kinase inhibitor developed by Day One Biopharmaceuticals. It is capable of inhibiting wild-type and certain mutant forms of BRAF, CRAF, and ARAF protein kinases.

RAF kinase is a key member of the RAS/RAF/MEK/ERK signaling pathway, including three subtypes: ARAF, BRAF, and CRAF, among which BRAF has the highest mutation frequency, accounting for more than 90% of all RAF mutations.Approximately7%In Human TumorsWillBRAF mutation occurs,It has a high mutation frequency in melanoma, approximately 50%-80%.

The approved 1st to 3rd generation RAF inhibitors can lead to drug resistance after prolonged use. To overcome this resistance, pan-RAF kinase inhibitors such as Tovorafenib from Day One Biopharmaceuticals are being developed.

On October 30, 2023, Day One Biopharmaceuticals announced that the FDA had accepted the NDA for Tovorafenib and granted priority review for the treatment of recurrent or progressive pediatric low-grade glioma (pLGG).FDA Sets PDUFA Goal Date for April 30, 2024.

In November 2023, Kilburn et al. reported the results of the Phase II FIREFLY-1 trial of Tovorafenib in the journal Nature Medicine: In patients with high-grade glioma (RANO-HGG) in neuro-oncology, the overall response rate (ORR) in the Tovorafenib treatment group was 67%, reaching the pre-specified primary endpoint for Cohort 1. Twelve patients achieved complete response, and 34 patients achieved partial response, with a median duration of response (DOR) of 16.6 months and a median time to response (TTR) of 3.0 months (Figure 3).^[5]。

In pediatric neuro-oncology patients with low-grade gliomas (RAPNO), the ORR was 51%, with 28 patients achieving partial response, a median DOR of 13.8 months, and a median TTR of 5.3 months (Figure 3).

Figure 3. FIREFLY-1 Trial Results

Patritumab deruxtecan

HER3 ADC

Patritumab deruxtecan (HER3-DXd) is an ADC drug targeting HER3 originally developed by Daiichi Sankyo. It is constructed by linking the HER3 monoclonal antibody patritumab with the topoisomerase I inhibitor deruxtecan via a maleimide-GGFG linker.

HER3 expression was observed in 83% of primary NSCLC tumors, including those with EGFR mutations (EGFRm).Compared with wild-type EGFR tumors, HER3 mRNA levels are elevated in EGFRm NSCLC tumors.In NSCLC, HER3 expression is associated with advanced disease, shorter metastasis time, and reduced survival rates.

Patritumab deruxtecan is currently the fastest-progressing HER3 ADC drug in development and has gained favor from Merck due to its excellent efficacy. On October 20, 2023, Merck and Daiichi Sankyo reached a cooperation agreement worth up to 22 billion US dollars for three ADC drugs, including Patritumab deruxtecan.

On December 22, 2023, Daiichi Sankyo and Merck jointly announced that the BLA for patritumab deruxtecan had been accepted by the FDA and granted priority review for the treatment of locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) patients who have received at least two prior systemic therapies, becoming the first HER3 ADC to be submitted for marketing.，FDA Sets PDUFA Date for June 26, 2024.

This BLA is based on the positive results of the Phase 2 HERTHENA-Lung01 trial, where the primary endpoint was ORR. In 225 patients with EGFR-mutated locally advanced or metastatic NSCLC who experienced disease progression after EGFR TKI and platinum-based chemotherapy, the ORR for patritumab deruxtecan was 29.8%, including one complete response and 66 partial responses (Figure 4).^[6]。

Figure 4. Clinical Trials of Patritumab Deruxtecan in Lung Cancer

In addition, Daiichi Sankyo/Merck is conducting multiple clinical trials to explore new indications for Patritumab deruxtecan, including melanoma, squamous cell carcinoma of the head and neck (SCCHN), HER2-negative gastric cancer, etc. (Figure 5).

Figure 5. Patritumab Deruxtecan Clinical Trial Protocol

Tarlatamab

DLL3/CD3 Bispecific Antibody

TArlatamab, developed by Amgen, is a bispecific T-cell engager (BiTE) class drug targeting DLL3 (delta-like ligand 3) and CD3. It recruits T cells to the vicinity of small cell lung cancer cells, activating T cells to kill tumor cells, and is used for the treatment of advanced small cell lung cancer (SCLC).

In May 2023, tarlatamab was approved for clinical use by the NMPA., intended for subjects with recurrent small cell lung cancer after receiving platinum-based first-line chemotherapy.

On December 13, 2023, Amgen announced that the BLA application for Tarlatamab had been accepted by the FDA and granted Priority Review for advanced SCLC.FDA Sets PDUFA Decision Date for June 12, 2024^[7]。

This BLA is based on the Phase II results of the DeLLphi-301 clinical trial: in patients with advanced SCLC whose disease progressed during or after platinum-based chemotherapy, the ORR reached 40% and 32% in the 10mg and 100mg groups, respectively, with a duration of response lasting at least 6 months. The progression-free survival (PFS) was 4.9 months and 3.9 months, respectively, and the overall survival rate (OS) at 9 months was projected to be 68% and 66%, respectively (Figure 6).^[8]。

Figure 6. DeLLphi-301 Clinical Trial Results

Fidanacogene elaparvovec

Novel Gene Therapy for Hemophilia B

Fidanacogene elaparvovec is a novel gene therapy developed by Spark Therapeutics. It contains a bioengineered adeno-associated virus (AAV) capsid and a high-activity variant of the human coagulation factor IX (FIX) gene, used for treating hemophilia B.

Patients with Hemophilia B lack clotting FIX, also known as congenital FIX deficiency or Christmas disease. According to the World Federation of Hemophilia, there were over 38,000 people worldwide living with Hemophilia B in 2021. The current standard of care requires repeated intravenous infusions of plasma-derived or recombinant FIX to control and prevent bleeding episodes.

In December 2014, Pfizer obtained a collaborative license for fidanacogene elaparvovec from Spark Therapeutics.RootAccording to the agreement, Spark Therapeutics is responsible for conducting all Phase 1/2 studies of the investigational gene therapy.Pfizer is responsible for key research, any regulatory activities, and potential global commercialization.

Fidanacogene elaparvovec has been granted Breakthrough Therapy, Regenerative Medicine Advanced Therapy (RMAT), and Orphan Drug designations by the FDA.

On June 27, 2023, Pfizer announced that the FDA had accepted the BLA for Fidanacogene Elaparvovec, intended for the treatment of adult patients with Hemophilia B.，FDA Sets PDUFA Goal Date for Q2 2024^[9]。

Meanwhile, the European Marketing Authorization Application (MAA) for Fidanacogene elaparvovec has been accepted and is currently under review by the European Medicines Agency (EMA).

This BLA is based on the efficacy and safety data from the Phase III BENEGENE-2 study (NCT03861273): The total bleeding rate (ABR) after Fidanacogene elaparvovec infusion showed non-inferiority and superiority compared to the FIX prophylaxis regimen (as part of routine care). Fidanacogene elaparvovec was generally well-tolerated, with safety consistent with Phase 1/2 results.

Danicopan

Oral Complement Alternative Pathway Factor D Inhibitor

Danicopan, an orally administered small molecule initially developed by Alexion, was acquired by AstraZeneca in 2020 for approximately $39 billion and is used to treat paroxysmal nocturnal hemoglobinuria (PNH).

PNH is a rare and serious blood disorder characterized by the destruction of red blood cells within blood vessels, known as intravascular hemolysis (IVH), and the activation of white blood cells and platelets, which can lead to thrombosis (blood clots), organ damage, and potentially premature death.

Approximately 10-20% of PNH patients treated with a C5 inhibitor will experience clinically significantExtravascular Hemolysis (EVH), which may lead to persistent anemia symptoms and the need for blood transfusions.

Danicopan selectively inhibits the alternative pathway of the complement system, blocks C3 convertase production, and controls extravascular hemolysis in PNH patients to treat PNH.

On June 9, 2023, AstraZeneca announced positive results from the pivotal Phase III ALPHA trial of Danicopan: in PNH patients experiencing clinically significant EVH, compared to placebo plus C5 inhibitor treatment,Danicopan plus C5 inhibitor therapy shows statistically significant and clinically meaningful increases in hemoglobin levels, and maintained disease control (Figure 7)^[10]。

Figure 7. Results of the ALPHA Trial

On January 18, 2024, danicopan was approved for marketing in Japan as an add-on therapy to standard-of-care complement factor C5 inhibitors Ultomiris (ravulizumab) or Soliris (eculizumab) for PNH patients experiencing significant EVH while on C5 inhibitor treatment.

This approval was based on the positive results of the Phase III ALPHA trial: compared with the placebo group, patients in the Danicopan group showed a statistically significant and clinically meaningful improvement in hemoglobin levels from baseline at week 12, achieving the primary endpoint. The study also met key secondary endpoints, including avoidance of transfusions and changes in FACIT fatigue scores.

Besides,Danicopan is also under review in the United States and the European Union and is expected to be approved for marketing this year.

Crovalimab

C5 Monoclonal Antibody

Crovalimab is a next-generation C5 inhibitor developed by Roche through continuous monoclonal antibody recycling technology, which can block the complement C5 from cleaving into C5s and C5b, and is expected to inhibit complement activation (Figure 8).

Figure 8. Mechanism of Action of Crovalimab

Compared with existing PNH therapies,Crovalimab can extend the dosing interval to once every 4 weeks via self-administered subcutaneous injection, enhancing the efficacy and convenience of existing PNH therapies.

On September 4, 2023, Roche announced that the FDA had accepted the BLA for crovalimab.If approved, crovalimab will become the first subcutaneous formulation therapy for PNH that requires dosing only once a month and can be self-administered by patients.

This BLA is based on the pivotal Phase III COMMODORE 2 study results: In patients with PNH, Crovalimab was non-inferior to Eculizumab in the co-primary endpoint of hemolysis control, achieving disease control and demonstrating good tolerability (Figure 9).^[11]。

Figure 9. COMMODORE 2 Trial Results

On February 8, 2024, crovalimab was approved for marketing in China., for the treatment of adult and adolescent patients with PNH who have not previously received complement inhibitor therapy(12 years oldAnd above)Patient.

KarXT

Compound preparation

Xanomeline-trospium (KarXT), developed by Karuna Therapeutics, is a potential "first-in-class" drug for the treatment of schizophrenia, followed byOn December 22, 2023, BMS acquired Karuna for $14 billion, bringing KarXT into its portfolio.

KarXT is a complex composed of the M1/M4 agonist xanomeline and the M receptor antagonist trospium.It aims to activate muscarinic acetylcholine receptors in the brain while reducing effects on peripheral muscarinic acetylcholine receptors, making it the first potential drug in its class with a truly novel and unique dual mechanism.

On November 29, 2023, Karuna Therapeutics announced that the U.S. FDA had accepted its NDA for KarXT for the treatment of adult schizophrenia.FDA Sets PDUFA Date for September 26, 2024，If approved, KarXT will be the first new pharmacological approach to treating schizophrenia in decades.^[12]。

This NDA submission was supported by the efficacy and long-term safety data from the EMERGENT program.Including three completed trials, EMERGENT-1, EMERGENT-2, and EMERGENT-3, which evaluated the efficacy and safety of KarXT compared to placebo, as well as EMERGENT-4 and EMERGENT-5, which assessed the long-term safety of KarXT.

In all three placebo-controlled trials, KarXT met its primary endpoint, demonstrating statistically significant and clinically meaningful improvements in schizophrenia symptoms compared to placebo, as measured by the total score of the Positive and Negative Syndrome Scale (PANSS).The study found that KarXT was generally well-tolerated, with the most common adverse events being cholinergic in nature and of mild to moderate severity.

In December 2023, Kaul et al. reported in The Lancet the results of the Phase III EMERGENT-2 trial on the efficacy and safety of KarXT in treating schizophrenia: The trial met its primary endpoint, with the KarXT group showing an average reduction of 21.2 points in PANSS total score from baseline by Week 5, compared to a 11.6-point reduction in the placebo group, resulting in a 9.6-point greater reduction in the KarXT group versus the placebo group (Figure 10).

At Week 5, compared with placebo, the KarXT group showed a 2.9-point reduction in the PANSS positive subscale score, a 1.8-point reduction in the PANSS negative subscale score, and a 2.2-point reduction in the PANSS Marder negative factor score (Figure 10).^[13]。

Figure 10. EMERGENT-2 Trial Results

Dato-DXd

Trop-2 ADC

Datopotamab Deruxtecan（Dato-DXd) is a humanized Trop-2 ADC jointly developed by Daiichi Sankyo and AstraZeneca, obtained by linking the antibody with a topoisomerase 1 inhibitor through a cleavable tetrapeptide linker.

As of now, only one Trop-2 ADC, Trodelvy, has been approved for marketing globally, used for the treatment of triple-negative breast cancer and urothelial carcinoma, among others. Related content expansion:The World’s First Marketed Trop-2 ADC "Sacituzumab Govitecan" Poised to Join the Billion-Dollar Molecule Club?

Unlike Trodelvy,AstraZeneca/Daiichi-Sankyo Plan to Launch Dato-DXd for Advanced Non-Small Cell Lung Cancer as the Initial Indication, transforming Dato-DXd into a potential alternative for NSCLC treatment chemotherapy.

Previously, the TROPION-Lung01 and TROPION-Lung02 trials evaluating the efficacy of Dato-DXd in treating NSCLC patients both yielded positive results.The results of the TROPION-Lung02 study showed that the ORR for Dato-DXd combined with immunotherapy or Dato-DXd combined with immunotherapy + chemotherapy in treating advanced NSCLC patients were 38% and 49%, respectively. The disease control rates (DCR) were 84% and 87%, respectively, and the median PFS was 8.3 months and 7.3 months, respectively.

In addition, Daiichi Sankyo/AstraZeneca has launched multiple clinical trials exploring new indications for Dato-DXd, including breast cancer, colorectal cancer, and urothelial cancer, among others.

The Phase III TROPION-Breast05 clinical trial of Dato-DXd in combination with Durvalumab for first-line treatment of PD-L1 positive metastatic triple-negative breast cancer was initiated in November 2023 (Figure 11).

Figure 11. TROPION-Breast05 Clinical Trial Design

Recently, in the financial report released by Daiichi Sankyo, the Phase III clinical trial plan for Dato-DXd as an adjuvant treatment for HR-low and HER2-low breast cancer patients was also disclosed, as shown in Figure 12.

Figure 12. Phase 3 Clinical Trial Design for Adjuvant Treatment of HR-low, HER2-low Breast Cancer Patients

On February 19, 2024, AstraZeneca/Daiichi-Sankyo announced that the BLA for Dato-DXd had been accepted by the FDA., for the treatment of adult patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have previously received systemic therapy,FDA Sets PDUFA Date for Q4 2024.

This BLA is based on the pivotal Phase III TROPION-Lung01 trial results, in which Dato-DXd demonstrated a statistically significant improvement in patients with locally advanced or metastatic NSCLC, showing a statistically significant progression-free survival (PFS), one of the dual primary endpoints, compared to docetaxel (the current standard of care).SignificantImprovement; the other primary endpoint, overall survival (OS), showed interim results numerically superior to docetaxel in the overall population. However, at the data cutoff, the results did not reach statistical significance.

Overall, in patients with non-squamous NSCLC, Dato-DXd demonstrated a clinically meaningful PFS benefit and a numerically favorable OS trend. The trial is ongoing, and OS will be assessed at the final analysis.

References (scrollable):

1.Stephen A. Harrison, Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial, Nature Medicine | Volume 29 | November 2023 | 2919–2928

2.Stephen A. Harrison et.al, A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis, N Engl J Med 2024; 390:497-509

3.Merck Receives Priority Review from FDA for New Biologics License Application for Sotatercept, an Activin Signaling Inhibitor to Treat Adults with Pulmonary Arterial Hypertension (PAH)

4.Role of Sotatercept in Management of Pulmonary Arterial Hypertension: The STELLAR Trial

5.Lindsay B. Kilburn et.al, The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial, Nature Medicine volume 30, pages207–217 (2024)

6.FY2023 Q3 Financial Results Presentation DAIICHI SANKYO CO., LTD.

7.FDA GRANTS PRIORITY REVIEW TO AMGEN'S TARLATAMAB APPLICATION FOR ADVANCED SMALL CELL LUNG CANCER

8.M.-J. Ahn et.al, Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer, N Engl J Med 2023;389:2063-75.

9.FDA Accepts Pfizer’s Application for Hemophilia B Gene Therapy Fidanacogene Elaparvovec

10.Danicopan as add-on to Ultomiris or Soliris improved haemoglobin levels and maintained disease control in patients with PNH experiencing signs or symptoms of clinically significant extravascular haemolysis

11.THE PHASE III, RANDOMIZED COMMODORE 2 TRIAL: RESULTS FROM A MULTICENTER STUDY OF CROVALIMAB VS ECULIZUMAB IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA PATIENTS NAIVE TO COMPLEMENT INHIBITORS

12.Karuna Therapeutics Announces U.S. Food and Drug Administration Accepts New Drug Application for KarXT for the Treatment of Schizophrenia

13.Inder Kaul, Sharon Sawchak, Christoph U Correll, Rishi Kakar, Alan Breier, Haiyuan Zhu, Andrew C Miller, Steven M Paul, Stephen K Brannan, Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebocontrolled, flexible-dose phase 3 trial

Columnist

May

Master and Ph.D. in Medicinal Chemistry, postdoctoral research abroad, currently engaged in drug development, passionate about the pharmaceuticals industry, eager to learn and grow with fellow professionals, and jointly witness the advancement of innovative drugs.

Disclaimer: The publication/reposting of this article is solely for the purpose of information dissemination, and does not represent the views of this public account or confirm the authenticity of its content. Any judgment made based on this content is at your own risk.If there is any infringement, please inform us and we will delete it immediately!

Press and hold to follow this official account

Fan Group/Submission/Authorization/Advertisementetc.

Please contact the official account assistant.

If you think this article is good-looking, please click here ↓