FDA Decisions Expected: December 2024 - Prime Therapeutics
FDA Decisions Expected
Drug pipeline for December 2024
Your monthly synopsis of new drugs expected to hit the market
At Prime Therapeutics (Prime), we have positioned ourselves to best prepare our clients to manage new drugs. Our clinical and trade relations teams keep a keen eye on drugs awaiting approval by the United States (U.S.) Food and Drug Administration (FDA).
Drug pipeline for December 2024
Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody that improves thrombin generation. Novo Nordisk is awaiting FDA approval of conzicumab for hemophilia A and B prophylaxis in patients with inhibitors. Concizumab was granted Breakthrough Therapy and Orphan Drug designations by the FDA. This is the second review for the product, after the FDA issued a complete response letter (CRL) in April 2023 requesting additional information related to its monitoring, dosing, and manufacturing. In the open-label, parallel-group, phase 3 EXPLORER 7 trial, concizumab led to a significant reduction in the estimated mean annualized bleeding rate (ABR) compared to no prophylaxis (1.7 versus 11.8, respectively; ABR ratio, 0.14; p< 0.001).1 If approved, concizumab will be the second anti-TFPI antibody available in the U.S., following the approval of marstacimab (Hympavzi) in October 2024 for hemophila A or B without inhibitors. Concizumab could also compete with emicizumab-kxwh (Hemlibra) in patients with hemophilia A. However, concizumab could face challenges in market uptake due to the need for daily subcutaneous (SC) injections (self-administered via auto-injector) and reports of non-fatal thrombosis that led to a clinical hold on the EXPLORER 7 trial. Notably, no thrombotic events or other safety concerns were reported with concizumab after new safety measures were adopted to mitigate this risk. Novo Nordisk also submitted concizumab for FDA approval for hemophilia A and B prophylaxis in patients without inhibitors. The FDA decision for this indication is expected in May 2025.
Dec. 1, 2024: denosumab (CT-P41)
Celltrion is awaiting FDA approval of CT-P41, a biosimilar candidate for the RANK ligand (RANKL) inhibitor denosumab. The reference product Prolia, by Amgen, is approved to treat osteoporosis or increase bone mass in select men and women who are at high risk for bone fracture. If approved, CT-P41 will be the second denosumab biosimilar to be approved in the U.S.
The FDA granted Neurotech’s gene therapy revakinagene taroretcel a Priority Review as well as Fast Track and Orphan Drug designations for the treatment of macular telangiectasia (MacTel) type 2, a rare ophthalmic neurodegenerative disorder. Revakinagene taroretcel is implanted into the vitreous of the eye during a single outpatient surgical procedure. It uses an encapsulated cell therapy (ECT) platform for sustained delivery of ciliary neurotrophic factor (CNTF) directly to the retina to slow the progression of the disease. In two double-blind, phase 3 trials, revakinagene taroretcel preserved photoreceptors by up to 56% compared to sham; however, the trials did not demonstrate a significant improvement in vision.2 If approved, revakinagene taroretcel will be the first treatment indicated for MacTel type 2.
For more information, see the revakinagene taroretcel Deep Dive in the October 2024 edition of Prime Therapeutics’ Quarterly Drug Pipeline Quarterly Drug Pipeline: October 2024 - Prime Therapeutics - Portal
Akcea and Ionis have submitted olezarsan to the FDA for the treatment of familial chylomicronemia syndrome (FCS), a rare, inherited disorder characterized by severe hypertriglyceridemia. Olezarsan is an RNA-targeted ligand conjugated antisense (LICA) agent that lowers plasma triglyceride (TG) levels by reducing hepatic synthesis of apolipoprotein C-III (apoC-III). It is administered via SC injection every four weeks. In the double-blind, phase 3 BALANCE trial, olezarsen led to a significantly greater reduction from baseline in fasting TG levels compared to placebo at six months in patients with confirmed FCS.3 Standard lipid-lowering medications (e.g., statins, fibrates, niacin) are not effective in lowering TG levels in patients with FCS. If approved, olezarsen will be the first agent available in the U.S. to treat FSC. The FDA has granted olezarsen Breakthrough Therapy, Fast Track and Orphan Drug designations and a Priority Review.
For more information, see the olezarsen Deep Dive in the October 2024 edition of Prime Therapeutics’ Quarterly Drug Pipeline Quarterly Drug Pipeline: October 2024 - Prime Therapeutics - Portal
Daiichi Sankyo and AstraZeneca are seeking approval of the trophoblast cell-surface antigen 2 (TROP2)-directed antibody drug conjugate (ADC) dato-DXd as a second-line treatment for locally advanced or metastatic, nonsquamous non-small cell lung cancer (NSCLC) and unresectable or metastatic, HR-positive/HER2-negative, breast cancer (immunohistochemistry [IHC] 0, IHC 1+ or IHC 2+/in situ hybridization-negative [ISH-]). In the open-label, phase 3 TROPION-Lung01 trial, dato-DXd reduced the risk of disease progression or death by 37% compared to docetaxel in treatment-experienced patients with locally advanced or metastatic NSCLC.4 After a median follow-up of 23.1 months, the median overall survival (OS) was numerically longer with dato-DXd compared to docetaxel (14.6 months versus 12.3 months, respectively) but the difference was not statistically significant. In addition, the ongoing, open-label, phase 3 TROPION-Breast01 trial reported dato-DXd reduced the risk of progression or death by 37% compared with investigator’s choice chemotherapy (ICC) in the breast cancer setting as described above.5 OS outcomes have not been reported due to immature data. Dato-dXd is administered via intravenous (IV) infusion every three weeks. If approved, dato-DXd will be the first TPOP2-targeted therapy for NSCLC and the second for breast cancer. It may directly compete with sacituzumab govitecan-hziy (Trodelvy) in the HR-positive/HER2-negative breast cancer setting where it may demonstrate a more favorable safety profile compared to Trodelvy.
For more information, see the datopotamab deruxtecan Deep Dive in the October 2024 edition of Prime Therapeutics’ Quarterly Drug Pipeline Quarterly Drug Pipeline: October 2024 - Prime Therapeutics - Portal
Glepaglutide is a long‐acting glucagon‐like peptide‐2 (GLP-2) analog by Zealand Pharmaceuticals awaiting FDA approval for the treatment of short bowel syndrome (SBS) in adults with intestinal failure. The FDA has granted glepaglutide an Orphan Drug designation. In clinical trials, glepaglutide was administered via SC injection once or twice per week. The double-blind, phase 3 EASE-1 trial demonstrated that after 24 weeks glepaglutide led to a reduction in total weekly volume of parenteral support (PS) from baseline by 3.13 liters (not statistically significant) with once-weekly doses and 5.13 liters (p=0.0039) with twice-weekly doses compared to 2.85 liters with placebo.6 Based on interim data from the EASE-2 and EASE-3 long-term extension trials, key efficacy endpoints, including PS reduction, were maintained or continued to improve with glepaglutide beyond the initial 24 weeks of treatment.7 If approved, glepaglutide will compete directly with once-daily SC doses of the GLP-2 analog teduglutide (Gattex) in adults with SBS who require PS. Glepaglutide is being developed as a liquid formulation in an auto-injector.
For more information, see the glepaglutide Deep Dive in the October 2024 edition of Prime Therapeutics’ Quarterly Drug Pipeline Quarterly Drug Pipeline: October 2024 - Prime Therapeutics - Portal
The FDA is reviewing Syndax’s oral menin inhibitor revumenib for the treatment of adult and pediatric patients with relapsed or refractory (R/R) KMT2A-rearranged (KMT2Ar) or mutant NPM1 acute leukemia. FDA granted Breakthrough Therapy, Fast Track and Orphan Drug designations for revumenib. While the FDA also granted it a Priority Review and a review under the Real-Time Oncology Review (RTOR) program, the agency extended the decision to Dec. 26, 2024. KMT2A rearrangement occurs in 80% of infant acute lymphoblastic leukemia (ALL) and in 5% to 15% of children and adults with acute leukemia (lymphoblastic, myeloblastic, mixed) and is associated a poorer prognosis. Mutated NPM1 is found in up to 30% of adult acute myeloid leukemia (AML). A phase 1/2, open-label, dose-escalation and expansion AUGMENT-101 study enrolled patients with acute leukemias as described above.8 It reported a complete remission or complete remission with partial hematologic recovery (CR/CRh) of 22.8% (primary efficacy endpoint). The overall response rate (ORR) was 63.2% (secondary endpoint). In the study, revumenib was administered orally every 12 hours in 28-day continuous cycles. If approved, it will be the first drug indicated to treat patients with KMT2Ar or mutated NPM1 acute leukemia.
The FDA granted a Priority Review for DCCR for the treatment of Prader-Willi syndrome (PWS) in individuals ages ≥ 4 years who have hyperphagia. PWS is a rare, genetic disorder with a hallmark feature of excessive hunger (hyperphagia) that can lead to severe obesity. DCCR, by Soleno, is a controlled-release tablet containing a crystalline salt of diazoxide that is administered orally once daily. The FDA granted the formulation Breakthrough Therapy, Fast Track and Orphan Drug designations for PWS. Notably, diazoxide is FDA approved as an oral suspension (Proglycem by Teva) for the management of hypoglycemia due to hyperinsulinism. Diazoxide is a potent activator of the ATP-sensitive potassium (KATP) channel resulting in a decrease in secretion of endogenous appetite stimulatory neuropeptides in the hypothalamus. DCCR was evaluated in the 13-week, double-blind, placebo-controlled C601 (DESTINY PWS) trial in people with PWS ages ≥ 4 years and in the open-label C602 extension study.9 Data from the PATH for PWS study served as an external natural history control. Investigators found that patients treated with DCCR in C601/C602 experienced significant improvements in hyperphagia compared to natural history, as measured by the Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) at 26 weeks (least square mean change from baseline, -8.3 points versus -2.5 points, respectively; p<0.001) and 52 weeks (least square mean change from baseline, -9.2 points versus -3.4 points, respectively; p<0.001); a reduction in HQ-CT score of at least 7 points was considered clinically meaningful. If approved, DCCR will be the first pharmacologic agent available to reduce hunger and improve food-related behaviors in patients with PWS.
Dec. 27, 2024: nivolumab/hyaluronidase (Opdivo SC)
Bristol Myers Squibb submitted nivolumab/hyaluronidase, a SC version of their programmed death-1 (PD-1) blocking antibody nivolumab (Opdivo). The company is pursuing approval for all the same indications that the Opdivo IV formulation holds, including, melanoma, colorectal cancer, NSCLC, mesothelioma, hepatocellular carcinoma, renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, and esophageal cancer, and gastric and gastroesophageal junction cancer. The SC formulation is injected by a health care professional over 3 to 5 minutes and has the potential for administration in the home. The IV formulation is administered over 30 to 60 minutes every two, three, or four weeks, depending on the indication and dose. If approved, this will be the second checkpoint inhibitor, following Tecentriq Hybreza, to be available as a SC formulation.
Dec. 27, 2024: ustekinumab (Bmab 1200)
Biocon is seeking FDA approval of Bmab 1200, an ustekinumab biosimilar candidate to Janssen’s Stelara. Stelara is a human interleukin-12, and -23 antagonist indicated of Crohn’s disease and ulcerative colitis in adults, and plaque psoriasis and psoriatic arthritis in adults and pediatric patients. If approved, Bmab 1200 will be the sixth biosimilar approved for Stelara.
Checkpoint Therapeutics resubmitted an application for its anti-programmed death ligand-1 (PD-L1) antibody, cosibelimab, for the treatment for adults with metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC) who are not candidates for curative surgery or curative radiation. The FDA had issued a CRL in December 2023 based on sight inspection deficiencies. Updated results from a phase 1 trial (NCT03212404) reported an ORR of 54.8% (complete response rate, 25.8%) in patients with locally advanced cSCC and an ORR of 50% (complete response rate, 12.8%) in those with metastatic cSCC; the median follow-up in each cohort was 24.1 and 29.3 months, respectively.10, 11 The median duration of response in either cohort was not yet reached. Cosibelimab was studied as 800 mg IV every two weeks or 1200 mg every three weeks. If approved, cosibelimab will be the third checkpoint inhibitor indicated for cSCC in the U.S., behind pemprolizumab (Keytruda; administered IV every three or six weeks) and cemiplimab-rwlc (Libtayo; administered IV every three weeks).
Ensartinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor, by Xcovery, under review for the treatment of adult patients with metastatic ALK-positive NSCLC. The phase 3, open-label eXalt3 trial reported that ensartinib led to a significantly longer primary endpoint of progression-free survival (PFS) compared to crizotinib (25.8 versus 12.7 months, respectively; p<0.001), including among patients with confirmed ALK-positive NSCLC (modified intent-to-treat [mITT] population) (median PFS, not reached versus to 12.7 months, respectively; p<0.001).12 secondary efficacy endpoints including overall survival (OS), overall and complete responses, and intracranial response. Ensartinib is administered orally once daily. If approved, it will join several other ALK-targeting tyrosine kinase inhibitors, including crizotinib (Xalkori) as a preferred treatment for ALK-positive NSCLC.
Jiangsu Vcare is seeking FDA approval for vicagrel to treat several thrombotic cardiovascular and cerebrovascular diseases, including acute coronary syndrome, ischemic stroke and peripheral arterial disease. Vicagrel is an oral P2Y12 receptor antagonist that uses the same metabolite as clopidogrel to inhibit platelet aggregation and activation. However, unlike clopidogrel, vicagrel can bypass the cytochrome P450 enzymes to provide more active metabolites compared to clopidogrel, whether this is clinically relevant has not been proven. Three dosages of vicagrel (5 mg, 6 mg, 7.5 mg) and one dose of clopidogrel (75 mg) were evaluated in a double-blind, triple-dummy, parallel-controlled, dose-finding, phase 2 trial (NCT03599284) conducted in China that enrolled adults with stable coronary artery disease, unstable angina, and myocardial infarction and planned percutaneous coronary intervention.13 The primary endpoint of inhibition of adenosine diphosphate (ADP)-induced platelet aggregation (IPA) at day 28 was comparable across all groups (30.19%, 35.02%, and 45.61% with vicagrel 5 mg, 6 mg, and 7.5 mg doses, respectively, and 32.55% with clopidogrel; p=0.0694). No differences in adverse events or bleeding were noted between the groups. If approved, vicagrel could be used as an alternative to clopidogrel in patients who are resistant to clopidogrel or at risk for drug interactions.
Crinecerfont is a first-in-class, oral, selective corticotropin-releasing factor type 1 receptor (CRF1) antagonist by Neurocrine. The FDA granted the product a Priority Review as well as Breakthrough Therapy and Orphan Drug designations for the treatment of classic congenital adrenal hyperplasia (CAH), a rare, genetic disorder characterized by a lack of cortisol and/or aldosterone and an excess of adrenal androgens in the body. Life-threatening (adrenal crisis) can occur if classic CAH is left untreated. Glucocorticoid therapy (GC) is currently the standard of care for classic CAH; however, high or supraphysiologic doses of GCs are often required. In the double-blind, placebo-controlled, phase 3 CAHtalyst trial, twice-daily oral doses of crinecerfont led to a significant reduction in CG dose from baseline.14 If FDA-approved, it would be the first non-GC therapy available in the U.S. for classic CAH, and it will be used as add-on to GC therapy.
For more information, see the crinecerfont Deep Dive in the October 2024 edition of Prime Therapeutics’ Quarterly Drug Pipeline Quarterly Drug Pipeline: October 2024 - Prime Therapeutics - Portal
References
1 EXPLORER 7 trial: https://www.nejm.org/doi/full/10.1056/NEJMoa2216455
2 Press release: https://www.businesswire.com/news/home/20221102005232/en
3 BALANCE trial: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2400201
4 TROPION-Lung-01 trial: https://ascopubs.org/doi/full/10.1200/JCO-24-01544
5 TROPION-Breast01 trial: https://ascopubs.org/doi/full/10.1200/JCO.24.00920
7 Press release: : https://www.globenewswire.com/news-release/2023/05/11/2666246/0/en/Zealand-Pharma-Announces-Financial-Results-for-the-First-Quarter-of-2023.html
8 AUGMENT-101 trial: https://ascopubs.org/doi/10.1200/JCO.24.00826
9 C601/C602 trials: https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-024-09536-x
11 Poster:https://checkpointtx.com/wp-content/uploads/2024/09/1136P_Cosibelimab_ESMO_2024_Poster.pdf
12 eXalt2 trial: https://jamanetwork.com/journals/jamaoncology/fullarticle/2783490
13 NCT03599284: https://clinicaltrials.gov/study/NCT03599284
14 CAHtalyst trial: https://pubmed.ncbi.nlm.nih.gov/38828955/