November 2023 decisions expected from the FDA

At Prime Therapeutics (Prime), we’ve positioned ourselves to best prepare our clients to manage new drugs. Our clinical and trade relations teams keep a keen eye on drugs likely to be approved by the U.S. Food and Drug Administration (FDA).

Drug pipeline for November 2023:

 November 2023: VLA1553 (chikungunya vaccine monovalent, live attenuated)
The FDA is reviewing Valneva’s chikungunya virus (CHIKV) vaccine, VLA1553. Chikungunya is a mosquito-borne viral illness, with low mortality and high morbidity, that can be found in 110 countries, including the US. In a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial (NCT04546724), 98.9% of adults achieved CHIKV neutralizing antibody levels after a single intramuscular (IM) VLA1553 dose. VLA1553 was generally safe and well-tolerated in adults.¹ The safety profile for VLA1553 in adolescents is consistent with that found in adults, based on data up to 29 days post-dose from in a similarly designed Phase 3 trial (NCT04650399).² If approved, VLA1553 will be the first CHIKV vaccine worldwide.

11/15/2023: DefenCath™ (taurolidine/heparin)
The FDA is reviewing CorMedix’s new drug application (NDA) resubmission of DefenCath, a catheter lock solution that contains the antimicrobial agent taurolidine and the anticoagulant heparin. In a randomized, double-blind, active control, Phase 3 LOCK-IT-100 trial (NCT02651428), when compared to heparin alone, DefenCath displayed a statistically significant 71% reduction in the risk of developing a catheter-related bloodstream infection (CRBSI) in patients receiving hemodialysis via a central venous catheter (CVC).³ The safety profile for DefenCath was comparable to heparin alone. DefenCath was granted Infectious Disease Product (QIDP) designation by the FDA.

 11/16/2023: TAK-755
Takeda is seeking FDA approval of TAK-755 for the treatment of congenital thrombotic thrombocytopenic purpura (cTTP), which is characterized by widespread thrombosis. The ultra-rare condition is caused by mutations in the ADAMTS13 gene leading to a deficiency of the ADAMS13 enzyme. TAK-755 is a recombinant ADAMTS13 protein that enables processing of  von Willebrand factor.⁴ Interim analysis of an open-label, Phase 3 trial (NCT03393975) revealed that after a mean exposure of 13.2 months, zero acute thrombotic thrombocytopenic purpura (TTP) episodes were reported with TAK-755 compared to one event with standard of care (SOC) plasma-based therapy. Treatment-emergent adverse events occurred less often with TAK-755 than with SOC (10.3% versus 50%, respectively). In the clinical trial, TAK-755 was administered intravenously (IV) every other week or once weekly. If approved, TAK-755 will be the first treatment that replenishes ADAMTS13 and addresses the underlying cause of cTTP.

11/17/2023: vonoprazan fumarate
The FDA is reviewing Phathom Pharmaceuticals’ vonoprazan fumarate for the treatment of erosive gastroesophageal reflux disease (GERD). In the randomized, double-blind, Phase 3 PHALCON-EE trial (NCT04124926), oral once-daily monotherapy with vonoprazan was found to be non-inferior to the proton pump inhibitor oral lansoprazole based on complete healing of erosive esophagitis by week 8 in Helicobacter pylori-negative adults.⁵ Vonoprazan is a first-in-class potassium-competitive acid blocker (PCAB). In May 2022, the FDA-approved vonoprazan co-packaged in combination with amoxicillin ± clarithromycin under the brand names of Voquezna^® Dual Pak and Voquezna Triple Pak for use for the treatment of H. pylori.⁶ However, the products have not been launched in the U.S. due to trace levels of a nitrosamine impurity, N-nitroso-vonoprazan (NVP), a potential human carcinogen, found in commercial batches in August 2022. This finding led the FDA not to take action on the initial application for vonoprazan monotherapy for erosive GERD.

11/23/2023: reproxalap
Aldeyra Therapeutics has submitted a NDA for their reactive aldehyde species (RASP) modulator, reproxalap ophthalmic solution, for the treatment of dry eye disease (DED). In the randomized, double-masked, parallel design, Phase 3 TRANQUILITY-2 trial (NCT05062330), reproxalap demonstrated superiority to vehicle base on Schirmer test (p=0.0001) and ≥ 10 mm Schirmer test responder proportions (p<0.0001) after a single day of dosing.⁷ Approval is in question, as a late-cycle review meeting with the FDA noted a lack of clinical evidence which may lead to a complete response letter (CRL).⁸

11/27/2023: nirogacestat
Nirogacestat, a selective, small molecule gamma secretase inhibitor by SpringWorks, is under review under the FDA’s Real-Time Oncology Review (RTOR) program for the treatment of desmoid tumors (aggressive fibromatosis) in adults. Desmoid tumors are rare, aggressive, locally invasive, soft tissue tumors. While they do not metastasize, there is a high rate of recurrence. The randomized, double-blind, placebo-controlled, Phase 3 DeFi trial (NCT03785964) revealed that twice daily oral doses of nirogacestat led to a 71% reduction in the risk of disease progression (p< 0.001) compared to placebo in adults with desmoid tumors, and the likelihood of being event-free at two years was 76% with nirogacestat compared to 44% with placebo. The objective response rate was 41% with nirogacestat compared to 8% with placebo (p<0.001), with complete response rates of 7% and 0%, respectively.⁸ Significant improvements in pain, symptom burden, physical function, and quality of life were also evident with nirogacestat compared to placebo. Diarrhea, nausea, fatigue, and ovarian dysfunction (among women of childbearing potential) were commonly (≥ 50%) reported with nicogacestat. Adverse effects led to discontinuation in 14% of patients treated with nirogacestat. If approved, nirogacestat will be the first pharmacologic treatment for desmoid tumors.

 11/27/2023: fruquintinib
The FDA is reviewing fruquintinib for the treatment of adults with previously treated metastatic colorectal cancer (CRC). Fruquintinib is being developed by Takeda and Hutchmed. It is a kinase inhibitor that selectively targets vascular endothelial growth factor receptors (VEGFR) -1, -2 and -3 and impedes new blood vessel growth (angiogenesis) of malignant tumors. In the global, randomized, double-blind, placebo-controlled, Phase 3 FRESCO-2 trial (NCT04322539), after a median follow-up of 11 months, the median overall survival was 7.4 months with once-daily oral doses of fruquintinib compared to 4.8 months with placebo (hazard ratio, 0.66; p<0.0001) among patients who received a median of four prior lines of systemic therapy for metastatic disease.⁹ Grade 3 or worse adverse events with fruquintinib included hypertension (14%), asthenia (8%), and hand-foot syndrome (6%). One death was reported in each group (fruquintinb, intestinal perforation; placebo, cardiac arrest). If approved, fruquintinib will likely compete with trifluridine/tipiracil or regorafenib in patients with refractory mCRC.

 References

1. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00641-4/fulltext
2. https://valneva.com/press-release/valneva-reports-positive-initial-phase-3-safety-data-in-adolescents-for-its-single-shot-chikungunya-vaccine-candidate
3. https://journals.lww.com/cjasn/fulltext/9900/taurolidine_heparin_lock_solution_and.236.aspx
4. https://journals.lww.com/kidney360/fulltext/2021/10000/safety_and_efficacy_of_tenapanor_for_long_term.9.aspx
5. https://www.globenewswire.com/news-release/2022/05/24/2449654/0/en/Phathom-Pharmaceuticals-Presents-Data-on-Novel-Potassium-Competitive-Acid-Blocker-PCAB-Vonoprazan-from-a-Range-of-Studies-at-Digestive-Disease-Week-DDW-2022.html
6. https://investors.phathompharma.com/news-releases/news-release-details/phathom-pharmaceuticals-provides-update-new-drug-application
7. https://www.businesswire.com/news/home/20220607006390/en
8. Aldeyra forewarns potential FDA rejection for dry eye med (fiercebiotech.com) https://www.nejm.org/doi/pdf/10.1056/NEJMoa2210140?articleTools=true
9. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00772-9/fulltext#:~:text=Fruquintinib%20treatment%20resulted%20in%20a,with%20refractory%20metastatic%20colorectal%20cancer