Keeping Track: US FDA Clears Santen’s Omlonti, Fennec’s Pedmark; Lilly’s Retevmo Adds Tumor-Agnostic Claim

The latest drug approval news and highlights from the Pink Sheet’s US FDA Performance Tracker

Two of the US FDA’s latest new product approvals, Santen Pharmaceutical Co., Ltd.’s Omlonti and Fennec Pharmaceuticals Inc.’s Pedmark, both overcame manufacturing-related complete response letters on their way to market.

The Japan-based ophthalmology specialist Santen is using contract manufacturing facilities to produce Omlonti for the US. Omlonti received a complete response letter in November 2021 after the agency found the contract facilities to be out of compliance with good manufacturing practices, and then won approval on the second review cycle.

The FDA identified deficiencies at the drug product manufacturer for Fennec Pharmaceuticals’ Pedmark, an IV drug to prevent chemotherapy-related ototoxicity in pediatric solid tumor patients, at inspections on two review cycles. CRLs followed in August 2020 and November 2021.

In other recent news, Eli Lilly and Company’s rearranged during transfection (RET) kinase inhibitor Retevmo joined the small group of targeted therapies with tumor-agnostic indications with accelerated approval for solid tumor patients with RET gene fusions who have no more satisfactory alternative options. Separately, the FDA converted one of Retevmo’s tumor-specific indications, for non-small lung cancer with RET gene fusions, from accelerated approval to full approval.

Omlonti Joins Growing Ophthalmology Pharmacopoeia

Santen and Ube Industries, Ltd.’s Omlonti (omidenepag isopropyl) became the second novel eye drug to clear the FDA this year when the agency approved the relatively selective prostaglandin E2 (EP2) receptor agonist on 22 September 2022 for reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

The IOP lowering pharmacopoeia is large, but Omlonti is the first therapy with its pharmacological action, which “increases aqueous humor drainage through the conventional (or trabecular) and uveoscleral outflow pathways,” Santen emphasized. “Multiple pathways may result in more fluid draining, and therefore potentially more IOP control.”

The Omlonti NDA rested on three randomized trials with a three-month double-masked treatment duration that compared omidenepag isopropyl with ocular antihypertensive mainstays timolol and latanoprost. “IOP reductions were observed for all treatment arms,” Santen summarized.

“In the Omlonti arm, the reduction in IOP ranged from 5-7 mm Hg across all three studies. The corresponding reductions for the timolol and latanoprost arms were 5-7 mm Hg and 6-8 mm Hg, respectively.”

The Japanese ophthalmology company gained a US beachhead in 2020 with the acquisition of Eyevance Pharmaceuticals LLC and its US commercial infrastructure. The company has a Japanese portfolio that it is working to introduce in the US; omidenapag isopropyl has been approved in Japan as Santen’s Eybelis since 2018.

Santen’s US offerings also include Verkazia (cyclosporine ophthalmic emulsion), approved in June 2021 for vernal keratoconjunctivitis in pediatric and adult patients. (Also see "Santen CEO's Clear Vision For World 'Built On Ability To See'" - Scrip, 8 Mar, 2022.)

Omlonti is at the front of a small wave of novel ophthalmic candidates. Bausch + Lomb Inc./Novaliq GmbH’s NOV03 (perfluorohexyloctane) water-free eyedrops for dry eye disease associated with Meibomian gland dysfunction has a 28 June 2023 user fee goal date.

Earlier this month, Tarsus Pharmaceuticals Inc.’s announced an NDA submission for TP-03 (lotilaner) for Demodex blepharitis, an eyelid margin disease, with a likely goal date in early September 2023. 

While Omlonti, NOV03 and TP-03 are small molecules, much of the recent US FDA approval activity in eye diseases has come from biologics.

The first ophthalmologic novel approval of 2022 was Genentech’s bispecific antibody Ang-2 and VEGF-A Vabysmo (faricimab-svoa), approved 28 January for neovascular age-related macular degeneration and diabetic macular edema.

Novartis’ VEGF inhibiting antibody fragment Beovu (brolucizumab-dbll) added a DME indication on 27 May 2022.

The biosimilar pipeline is contributing new versions of established VEGF inhibitors, with Bioeq IP AG/Coherus BioSciences, Inc./Formycon AG’s Cimerli (ranibizumab-eqrn) earning the first interchangeable designation for a biosimilar version of Genentech, Inc. ’s Lucentis (ranibizumab) for retinal vascular disorders on 2 August 2022. (Also see "Coherus Biosimilar Used ‘Scientific Justification’ To Skip Switch Study, Still Get Interchangeability With Lucentis" - Pink Sheet, 31 Aug, 2022.)

Fennec’s Pedmark Hits The Mark With Broad Label

The FDA approved Pedmark (sodium thiosulfate) on 20 September 2022 to reduce the risk of ototoxicity associated with cisplatin in pediatric patients one month and older with localized, non-metastatic solid tumors. Infants younger than one month old have an increased risk of hypernatremia.

Pedmark is the first drug for its indication, although the product is Fennec’s “unique formulation” of the industrial chemical sodium thiosulfate, which has been used as an anti-drug toxicity agent and preservative. Pedmark is packaged in single-dose ready-to-use vials for IV administration after the completion of each cisplatin infusion.

“Cisplatin-induced ototoxicity is caused by irreversible damage to hair cells in the cochlea hypothesized to be due to a combination of reactive oxygen species (ROS) production and direct alkylation of DNA leading to cell death,” labeling explains.

“Sodium thiosulfate interacts directly with cisplatin to produce an inactive platinum species.” The drug also increases antioxidant glutathione levels and inhibits intracellular oxidative stress.

Fennec Pharmaceuticals noted that chemotherapy regimens for pediatric solid tumors now carry five-year survival rates of 85% or higher, but are still largely platinum-based and ototoxic. “Permanent hearing loss can be seen in approximately 60% of children treated with cisplatin and can be as high as 90%,” Fennec said. (Also see "Fennec Prepared For Market As Pedmark Finally Gets FDA Nod" - Scrip, 21 Sep, 2022.)

Two pivotal Phase III trials supported the new indication: SIOPEL 6, which enrolled 114 patients with standard risk hepatoblastoma (SR-HB) undergoing perioperative cisplatin-based chemotherapy, and the Children’s Oncology Group study COG ACCL0431, which enrolled 125 pediatric solid tumor patients undergoing chemo with cumulative cisplatin doses of 200mg/m2 or higher. Efficacy in the COG trial was evaluated in a subset of 77 patients with localized, non-metastatic solid tumors.

The Phase III SIOPEL 6 trial was the primary support for Pedmark’s breakthrough therapy designation, received in 2018 for a more limited claim of prevention of cisplatin-related ototoxicity in pediatric SR-HB patients. Among the SR-HB patients who received Pedmark and cisplatin, the incidence of hearing loss was 39%, compared with 68% in the cisplatin alone arm, the FDA summarized.

In the COG trial, 44% of the solid tumor patients who received Pedmark after cisplatin showed hearing loss, compared with 58% in the cisplatin-only arm.

Reflecting the COG protocol, Pedmark is to be administered only after cisplatin infusions of one to six hours in duration. A limitation of use in labeling notes that Pedmark may not reduce ototoxicity risk when administered following cisplatin infusions longer than six hours, “because irreversible ototoxicity may have already occurred.”

LIBRETTO Trial Scores Two More Retevmo Approvals

Lilly subsidiary Loxo Oncology’s Retevmo (selpercatinib) gained an accelerated approval for a new tumor-agnostic indication and graduated from accelerated to full approval in one of its original indications, RET-fusion NSCLC.

The applications followed different trajectories to approval on 21 September 2022. The sNDA covering solid tumors with RET gene fusions received priority review and was approved after a four-month review; the conversion from accelerated to full approval in RET fusion-positive NSCLC took the full 10 months for a standard review.

The Center for Drug Evaluation and Research decisions were accompanied by the approval of a companion diagnostic, Thermo Fisher Scientific’s next-generation sequencing (NGS)-based Oncomine Dx Target Test, to identify patients with RET-fusion positive NSCLC, RET-fusion positive thyroid cancer and RET-mutation positive medullary thyroid cancer who are eligible for Retevmo.

Previously, Retevmo labeling reported that “an FDA-approved test for the detection of RET gene fusions and RET gene mutations is not currently available” and pointed patients to tumor specimen or plasma testing.

Lilly’s marketing plan for Retevmo has long hinged on growing uptake of NGS; the company’s most recent approval announcement reiterates “the importance of routine, comprehensive genomic testing for patients across a wide variety of tumor types.” (Also see "Keeping Track: Targeted Oncologics Take Center Stage, Led By Retevmo And Tabrecta Approvals" - Pink Sheet, 11 May, 2020.)

All of Retevmo’s indications, new and original, are supported by cohorts from Loxo’s Phase I/II LIBRETT0-001 basket trial in RET-driven cancers. The study, which started in 2017, is designed to enroll 875 patients with solid tumors with RET fusion or activation in seven cohorts, including thyroid cancer and NSCLC.

LIBRETTO-001 acted as the both the pivotal study for the 8 May 2020 accelerated approval of Retevmo for metastatic RET fusion-positive NSCLC and as the confirmatory evidence for the conversion to full approval.

The original accelerated approval was based on initial overall response rate and duration of response in 144 LIBRETTO patients, the FDA noted, while “the conversion to regular approval was based on data from an additional 172 patients and 18 months of additional follow-up to assess durability of response.”

For the 316-patient efficacy set for full approval, the objective response rate was 61% in the 247 platinum-experienced NSCLC patients and 84% in the 69 treatment-naïve patients, the FDA summarized. The duration of response was 28.6 months in the previously treated group and 20.2 months in the first-line group.

The tumor agnostic indication specifies adults with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

The approval rests on 41 patients from a tumor-agnostic cohort of LIBRETTO-001, which included RET fusion-positive tumors other than NSCLC and thyroid cancer; pancreatic adenocarcinoma and colorectal cancers were the most common, each accounting for about one-quarter of the patients. The ORR for the tumor-agnostic patients was 44%, with a 24.5 month duration of response.

“The efficacy evaluation was supported by data in 343 patients with RET fusion-positive NSCLC and thyroid cancer enrolled in the same trial already described in product labeling,” the FDA added.

As a condition of the accelerated approval, Lilly must complete trials “to obtain data on the clinical efficacy of selpercatinib through more precise estimation of the overall response rate and mature response duration,” the approval letter states.

The data must come from at least 60 patients who progressed on prior systemic treatment or have no satisfactory alternatives to treat their locally advanced or metastatic RET-fusion positive solid tumors; while NSCLC and thyroid cancers are to be excluded, the study should enroll tumor types requiring additional characterization, such as colorectal cancer, esophagogastric cancer and glioma, the FDA said.