Sling Therapeutics, Inc. recently announced the closing of $123 million Series C financing and dosing of the first patients in the global phase 3 ORBIT pivotal trial evaluating linsitinib in adults with moderate to severe thyroid eye disease (TED).
First up: this company.
Launched in 2022 and based in Ann Arbor, Michigan, the late-stage biopharmaceutical company is currently focused on TED, specifically.
- Its lead investigational candidate: Linsitinib, an oral small molecule
A note on this candidate: Following a recent meeting with the FDA, linsitinib has received Fast Track designation—which qualifies Sling for more frequent interactions with the FDA regarding linsitinib’s clinical development program—alongside eligibility for Rolling Review, Accelerated Approval, and Priority Review, if relevant criteria are met.
Before we get into that, talk about this financing.
The company’s latest round of financing was led by Forbion, with participation from existing investor TPG Life Sciences Innovations and new investor Sectoral Asset Management.
- The purpose: To support the continued clinical advancement of linsitinib.
Also worth noting: In conjunction with the financing, the company made to appointments to its Board of Directors:
- Regina Salvat, PhD, of Forbion
- François Beaubien, PhD, CFA of Sectoral Asset Management
“With the support of a high-quality investor syndicate, we are well positioned to advance linsitinib toward commercialization with urgency and purpose for the TED community,” explained Ryan Zeidan, PhD, president and CEO of Sling Therapeutics.
Let’s get some details on this therapeutic, please.
Referred to as a “convenient oral small molecule,” linsitinib is designed to be taken twice a day (BID) and has a short half-life—intended to enable easier management of adverse events (AEs), according to Sling.
How it works: By blocking insulin-like growth factor 1 receptor (IGF-IR), known to be overexpressed in TED and the only “clinically validated” target for treatment of the disease.
- Some background: When activated, IGF-IR can cause such symptoms as inflammation and proptosis that are characteristic of TED.
So how does this stack up to other TED treatments?
Amgen’s Tepezza (teprotumumab-trbw), a monoclonal (mAb) IGF-IR antibody that reduces disease activity, proptosis, and diplopia, is the first FDA-approved treatment for TED.
- Its recommended dosage: 10 mg/kg intravenously injected into the arm followed by a second 20 mg/kg injection every 3 weeks for seven additional infusions (with each ranging from 60 to 90 minutes).
Compare this to linsitinib’s BID dosing schedule, and Sling may have an advantage over Amgen’s therapeutic.
Perhaps not for long, though: A randomized phase 3 trial evaluating Tepezza in a subcutaneous formulation (potentially enabling more rapid drug delivery) is currently ongoing …
Aren’t there other FDA-approved treatments for TED?
You would be correct. In June, the FDA approved Viridian’s LUMVOA for active and chronic TED—and that same company is also evaluating ELEGROBART for chronic TED (see its latest phase 3 data).
Plus, Genentech’s sBLA for ENSPRYNG (satralizumab)—which received FDA priority review—is expected to receive a regulatory decision next month (Oct. 15).
So what does this mean?
To put it bluntly: TED patients have many options in the pipeline.
Interesting … now talk about linsitinib’s clinical data.
The phase 2b LIDS trial (NCT05276063), which enrolled 90 patients diagnosed with active, moderate to severe TED, met its primary endpoint, with a statistically significant and meaningful proptosis reduction rate (PRR) observed for patients (n = 29) in the 150 mg linsitinib group.
- PRR = 52% (p = 0.01) at Week 24
In terms of safety: The therapeutic was “well-tolerated and consistent with the safety profile” of its previous clinical performance.
The following IGF-1R-targeted areas of interest were also noted for patients in the 150 mg linsitinib group:
- No reports of drug-related hearing impairment
- 0% tinnitus placebo-adjusted rate
- 3% rate of hyperglycemia
- 0% reports of menstrual cycle changes
And looking at AEs specifically …
The majority of AEs were mild or moderate, reversible, and resolved quickly “upon treatment pause or discontinuation consistent with a shorter half-life treatment,” Sling reported.
Treatment-emergent AEs ≥ 10% included:
- Diarrhea (20.7%)
- Headache (20.7%)
- Fatigue (17.2%)
- Alanine aminotransferase (ALT) increase (17.2%)
- Hyperhidrosis (13.8%)
- Aspartate aminotransferase (AST) increase (10.3%)
- Muscle spasms (10.3%)
Moving on to this new phase 3 trial.
Alignment on the pivotal phase 3 study design was secured during a successful end-of-phase 2 meeting with the FDA earlier this year.
ORBIT (NCT07753603) is expected to enroll approximately 130 participants, randomized 1:1 to receive oral linsitinib 150 mg or placebo (BID) for 24 weeks.
Following the 24-week double-masked placebo-controlled treatment period, patients will be eligible to enroll in a 24-week open-label extension.
What are the main outcome measures?
The primary endpoint is the proportion of proptosis responders at Week 24, defined as participants achieving a reduction of at least 2 mm in proptosis in the study eye without a corresponding worsening in the fellow eye.
Secondary endpoints include the mean change from baseline in:
- Proptosis
- Overall responder rate
- Clinical Activity Score (CAS)
- Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire
Any comments from the company?
“Early treatment [in TED] is critical, yet many patients remain untreated due to limitations of currently available therapies, including concerns about long-term hearing loss and the burden of traveling to infusion centers,” said Raymond Douglas, MD, PhD, board-certified aesthetic and reconstructive oculoplastic surgeon.
He added: “An effective oral therapy such as linsitinib could help address these barriers and meaningfully expand access to treatment.”
Lastly, when can we expect an update?
Though the study’s estimated primary completion date is June 30, 2028, we’ll likely hear updates before then.
Stay tuned!