November 2021 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).

11/6/2021: ET-101 (topiramate oral solution)
Azurity Pharmaceuticals’ ET-101 is seeking approval from the FDA as an oral liquid formulation of the anticonvulsant for monotherapy treatment of partial-onset or primary general tonic-clonic seizures in pediatric patients aged two years and older; for adjunctive therapy for partial-onset seizures, including Lennox-Gastaut syndrome, in patients aged two years and up; and for preventative treatment of migraine in patients 12 years and older. ET-101 is applying via the 505(b)(2) pathway using Janssen’s Topamax^® (topiramate) as its reference product.¹ Similar products include generic topiramate tablets.

11/7/2021: LIQ861
The FDA is reviewing Liquidia’s LIQ861, a dry powder for inhalation of treprostinil for enhanced deep-lung delivery in patients with pulmonary arterial hypertension (PAH). LIQ861 is seeking approval via the 505(b)(2) pathway using United Therapeutics’ Tyvaso^® (treprostinil) inhaled solution as its reference drug. In a clinical trial, INSPIRE, LIQ861 met its primary endpoint of safety and being well-tolerated in 109 treated patients.² Similar products include United Therapeutics’ Tyvaso^® (treprostinil), United Therapeutics’ Orenitram^® (treprostinil extended-release tablets), and United Therapeutics’ Remodulin^® (treprostinil injection).

11/12/2021: Zimhi^® (naloxone pre-filled syringe)
Adamis’ Zimhi is being reviewed by the FDA as a pre-filled single-dose syringe (PFS) formulation of high-dose naloxone for treatment of opioid overdose. Zimhi was originally submitted to the FDA using pharmacokinetic studies comparing Zimhi injection to a generic naloxone comparator in 2018. However, in 2019 Adamis received a complete response letter (CRL) from the FDA with concerns about chemistry manufacturing and controls (CMC) information.³ Adamis requested a Type A meeting with the FDA. In May 2020, Adamis resubmitted the updated NDA to the FDA but received a second CRL in November 2020. According to the statistics published by the Centers for Disease Control and Prevention, drug overdoses resulted in approximately 72,000 deaths in the United States in 2017. Similar products include Kaleo’s Evzio^® (naloxone) and Emergent’s Narcan^® (naloxone).

11/14/2021: ropeginterferon alfa-2b
PharaEssentia’s ropeginterferon alfa-2b is being evaluated by the FDA for patients with polycythemia vera (PV) in the absence of symptomatic splenomegaly. Ropeginterferon alfa-2b is a long-acting mono-pegylated proline interferon that is designed to increase convenience and has pharmacokinetic properties compared to conventional interferons. It is administered once every two weeks or once every four weeks during long-term maintenance. Ropeginterferon alfa-2b is seeking approval based on the Phase 3 PROUD/CONTI-PV trial in which patients with PV were treated with either ropeginterferon alfa-2b or hydroxyurea. At 36 months, the complete hematological response rate was much higher in the ropeginterferon alfa-2b group compared to the patients receiving hydroxyurea (70.5% versus 51.4% respectively).⁴ Additionally, 66% of patients treated with ropeginterferon alfa-2b reached a molecular response compared with 27% of patients treated with hydroxyurea.

11/20/2021: vosoritide
Biomarin Pharmaceuticals’ vosoritide, a C-type natriuretic peptide (CNP) analog which is administered as a once-daily subcutaneous injection for treatment of pediatric patients with achondroplasia is being reviewed by the FDA. Vosoritide is seeking approval based on a one year, Phase 3 clinical trial that demonstrated children treated with vosoritide had an average growth velocity of 1.57cm per year higher than the placebo group.⁵ The trial’s length and endpoints were not designed to detect improvements in long-term complications. There are currently no approved pharmacological treatments for achondroplasia, with existing treatments mainly limited to surgical interventions to address a variety of symptoms.⁶

11/21/2021: maribavir
The FDA is reviewing Takeda’s maribavir for cytomegalovirus infection in those that are refractory with or without resistance, in solid organ transplant or hematopoietic cell transplant recipients for oral treatment of post-transplant cytomegalovirus (CMV) infection in those that are refractory with or without resistance (R/R) to prior anti-CMV treatment in solid organ transplant or hematopoietic cell transplant (HCT) recipients.  Maribavir is seeking approval based on a Phase 3 clinical trial, SOLSTICE that demonstrated Maribavir’s superiority compared to conventional antiviral therapies in this patient population. The study’s primary endpoint was defined as the proportion of patients who achieved confirmed CMV viremia clearance compared to investigator-assigned antiviral therapy (IAT) at the end of eight weeks. Data showed that 55.7% of transplant recipients with R/R CMV infection/disease treated with maribavir achieved confirmed CMV viremia clearance at week 8 compared to 23.9% on conventional antiviral therapies.⁷ Similar products include generic ganciclovir, valganciclovir and Merck’s Prevymis^® (letermovir).

11/26/2021: Fyarro^® (sirolimus albumin-bound nanoparticles for injectable suspension, also known as nab-sirolimus or ABI-009)
Aadi Bioscience’s Fyarro has been granted priority review from FDA for treatment of patients with metastatic or locally advanced malignant perivascular epithelioid cell tumor (PEComa), a rare form of sarcoma. Fyarro is seeking approval based on clinical study that demonstrated an overall response rate (ORR) of 39%, including one complete response (CR) and 11 partial responses (PRs). The median duration of response had not yet been reached, ranging from 5.6 to 42.4 or more months, with 50% of the responders having a response duration that is 25.8 months or longer and the majority of the responders still on treatment. The response rate in the patients with metastatic disease was 46%. The median progression-free survival was 8.9 months, and the one-year overall survival rate was 89%.⁸ In an exploratory analysis of the subset of patients with TSC1 or TSC2 alterations, the independently reviewed response rate was 64%. Currently there are no FDA-approved products for this indication.

11/27/2021: Pedmark^® (sodium thiosulfate, STS)
Fennec Pharmaceuticals’ Pedmark is being reviewed by the FDA as an intravenous (IV) formulation of the thiol compound that acts as a chemical reducing agent for prevention of ototoxicity induced by cisplatin chemotherapy in pediatric patients one month to less than 18 years of age with localized, non-metastatic solid tumors. Pedmark is seeking approval based on two Phase 3 clinical studies, ACCL0431 and SIOPEL 6. ACCL0431 demonstrated hearing loss that was found to be significantly lower in the Pedmark group compared to control group after adjusting for stratification variables (28.6% Pedmark compared to 56.4% in control group). SIPEL 6 demonstrated hearing loss was significantly less with Pedmark compared to cisplatin alone (33% compared to 63%) which demonstrated a 48% lower incidence of hearing loss. Additionally, the three-year rate of event-free survival was 82% for the cisplatin-sodium thiosulfate group and 79% for the cisplatin alone group; overall survival was 98% and 92%, respectively.⁹ Similar products include STS.

11/27/2021: BAT1706 Avastin biosimilar
Bio-Thera Solutions’ BAT1706 is seeking approval from the FDA as an Avastin (bevacizumab) biosimilar. The BLA seeks approval of BAT1706 for the following indications: treatment of patients with metastatic colorectal cancer in combination with fluorouracil-based chemotherapy, first-line treatment for patients with non-squamous non-small cell lung cancer, recurrent glioblastoma, metastatic renal cell carcinoma in combination with interferon alfa and persistent, recurrent or metastatic cervical cancer. The BLA submission is based on data from a series of preclinical comparison studies, clinical pharmacokinetic comparison studies, and an international multi-center Phase 3 clinical comparison study that demonstrated that BAT1706 is highly similar to reference bevacizumab in clinical efficacy, safety, and immunogenicity.¹⁰ Similar products include Genentech’s Avastin^® (bevacizumab).

11/19/2021: omidenepag isopropyl
Santen and Ube Industries’ omidenepag isopropyl is applying for approval from the FDA for treatment of patients with glaucoma and ocular hypertension. Omidenepag isopropyl is a selective EP2 receptor agonist formulated as a topical ophthalmic solution as an ocular hypotensive. Omidenepag isopropyl is seeking approval based on two Phase 3 trials, SPECRUM 3 and SPECRUM 4 that demonstrated omidenepag isopropyl is non-inferior to twice daily timolol maleate 0.5% ophthalmic solution in reducing intraocular pressure (IOP) after three months.¹¹ Similar products Pfizer’s Xalatan^® (latanoprost) and Novartis’ Travatan Z^® (travoprost ophthalmic solution).

11/29/2021: ciltacabtagene autoleucel (cilta-cel)
The FDA is reviewing Janssen’s ciltacabtagene autoleucel (cilta-cel) for treatment of relapsed and refractory multiple myeloma. Ciltacabtagene autoleucel is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapy. Phase 1b/2 CARTITUDE-1 trial demonstrated ciltacabtagene autoleucel had an ORR of 97.9% with an 80.4% rate of stringent complete response (sCR).¹² At 18 months, 66% of patients were alive and progression free with an sCR of 75.9%. Similar products include Bristol Myers Squibb’s Abecma^® (idecabtagene vicleucel).

11/30/2021: plinabulin
The FDA is reviewing BeyondSpring’s plinabulin in combination with granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia (CIN). Plinabulin, a novel, intravenous infused small molecule, acts as a selective immunomodulating microtubule-binding agent (SIMBA), with immune anti-cancer activities, and broad activities in prevention of CIN across chemotherapy and cancer types. In the Phase 3 trial, the plinabulin arm had superior CIN benefit versus pegfilgrastim alone in patients with breast cancer to mitigate neutropenic effects of docetaxel, doxorubicin, and cyclophosphamide (TAC). The primary end point of improved grade 4 neutropenia in cycle 1 was meet, with patients on plinabulin at 13.6% versus 31.5% with the control.¹³ Similar products include Amgen’s Neulasta^® (pegfilgrastim).

11/30/2021: pacritinib
CTI BioPharma’s pacritinib is seeking priority review from the FDA for treatment for myelofibrosis patients with severe thrombocytopenia (platelet counts less than 50 x 109/L). Pacritinib is an oral kinase inhibitor with specificity for JAK2, IRAK1, and CSF1R. The FDA decision will be made based on results from the Phase 3, PERSIST-2 and PERSIST-1 trials. PERSIST-2 demonstrated that pacritinib at 200mg twice daily was significantly more effective in treating patients with myelofibrosis and thrombocytopenia than the existing best available therapies. The results suggest that pacritinib can provide an alternative treatment option for patients whose options are limited.¹⁴ Specifically, a reduction in spleen volume of at least 35% was observed in 29% of patients treated with pacritinib compared with only 3% of patients treated with the best available therapy. Similar products include Incyte’s Jakafi^® (ruxolitinib).

11/30/2021: Filsuvez^® (oleogel-S10 formerly AP101)
Amryt Pharma’s Filsuvez is seeking approval from the FDA for treatment of cutaneous manifestations of Junctional and Dystrophic Epidermolysis Bullosa. Filsuvez is a topical gel that can be applied at home. Filsuvez’s application was based on Phase 3, EASE trial that met its primary endpoint by demonstrating a statistically significant increase in speed of wound healing in EB with a complete closure of the target wound within 45 days compared to placebo.¹⁵ Several secondary measures were missed including 90-day target wound closure, and the pain endpoint. Current treatments aim to help alleviate symptoms, including bandaging and bathing open wounds and trying to manage patients’ pain, but there are no FDA-approved products for this indication.

While the information in this newsletter is from sources we believe to be reliable, we do not warrant that the information in this document is free from error. Use it only as a guide. Statements regarding drugs or manufacturers are not intended as promotion; those statements should not be used to make assumptions about formulary status. Each trademarked drug name is the property of its respective owner.

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References

1. https://www.globenewswire.com/en/news-release/2020/10/06/2104593/0/en/Eton-Pharmaceuticals-Submits-New-Drug-Application-to-the-FDA-for-Topiramate-Oral-Solution-ET-101.html
2. https://www.globenewswire.com/news-release/2021/05/10/2226074/0/en/Liquidia-Resubmits-New-Drug-Application-for-LIQ861-treprostinil-Inhalation-Powder-for-the-Treatment-of-Pulmonary-Arterial-Hypertension.html
3. https://www.empr.com/home/news/fda-accepts-resubmitted-zimhi-nda-for-opioid-overdose-treatment/
4. https://www.targetedonc.com/view/bla-resubmission-for-ropeginterferon-alfa-2b-accepted-by-fda-for-treatment-of-patients-with-pv
5. https://www.fiercebiotech.com/biotech/biomarin-nabs-fda-review-for-dwarfism-drug-vosoritide-forgoes-adcomm-as-it-eyes-2021
6. https://www.prnewswire.com/news-releases/biomarin-completes-full-enrollment-in-phase-2-study-of-vosoritide-for-treatment-of-infants-and-young-children-with-achondroplasia-301239664.html
7. https://www.takeda.com/newsroom/newsreleases/2021/takedas-maribavir-phase-3-clinical-trial/
8. https://www.globenewswire.com/en/news-release/2021/06/04/2242130/0/en/Aadi-Bioscience-Presents-Emerging-Data-for-FYARRO-in-Patients-with-Solid-Tumors-Harboring-TSC1-or-TSC2-Inactivating-Alterations-from-a-Multi-Institution-Expanded-Access-Program-at-.html
9. https://www.empr.com/home/news/drugs-in-the-pipeline/pedmark-receives-priority-review-for-prevention-of-cisplatin-induced-ototoxicity/
10. https://www.businesswire.com/news/home/20210128005703/en/Bio-Thera-Solutions-Announces-FDA-Accepts-Biologics-License-Application-for-BAT1706-a-Proposed-Biosimilar-to-Avastin%C2%AE
11. https://www.prnewswire.com/news-releases/santen-announces-initiation-of-phase-3-clinical-development-program-spectrum-in-the-united-states-evaluating-omidenepag-isopropyl-de-117-for-the-treatment-of-glaucoma-or-ocular-hypertension-300735092.html
12. https://www.businesswire.com/news/home/20210201005446/en/Janssen-Announces-CAR-T-Therapy-Ciltacabtagene-Autoleucel-Cilta-cel-Accepted-for-Accelerated-Assessment-in-Europe-for-the-Treatment-of-Patients-with-Heavily-Pretreated-Multiple-Myelom
13. https://www.cancernetwork.com/view/plinabulin-plus-g-csf-earn-priority-review-from-fda-for-cin
14. https://www.cancernetwork.com/view/fda-grants-priority-review-to-pacritinib-for-treating-myelofibrosis-with-severe-thrombocytopenia
15. https://www.globenewswire.com/en/news-release/2020/10/29/2116547/0/en/AMRYT-ANNOUNCES-POSITIVE-RESULTS-FROM-PHASE-3-TRIAL-OF-FILSUVEZ-IN-EPIDERMOLYSIS-BULLOSA.html