Spiral Therapeutics

Discussion in 'Research News' started by Michael Larsen, Sep 30, 2017.

    1. Michael Larsen

      Michael Larsen Member

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    2. Iliasp

      Iliasp Member

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      Acoustic trauma, Hearing loss
      Any papers on that?
    3. acufenero

      acufenero Member

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    4. Aaron123

      Aaron123 Member

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      There's very little on Spiral. They've been mentioned here a few times:


      There are a couple of abstracts from poster presentations at conferences. From what I can tell, the authors do not appear to be employees of Loop or Spiral Therapeutics, but the poster abstracts do refer to LPT99.

      Inhibition of APAF-1 with LPT99 prevents cisplatin-induced hearing loss
      Hearing loss is a common severe adverse effect of chemotherapy with platinum agents, especially cisplatin. Cisplatin induces the depletion of glutathione and antioxidant enzymes, leading to accumulation of reactive oxygen species in the cochlea, which trigger the intrinsic apoptotic pathway in hair cells. The apoptosis protease-activating factor-1 (APAF-1) binds to cytochrome c to form the apoptosome, which recruit procaspase-9 and activates effector caspases. APAF-1 inhibition has been previously validated as therapeutic strategy for the prevention of unwanted apoptosis. Here we evaluate the in vivo therapeutic effect of LPT99, a second generation APAF-1 inhibitor with good cochlear permeability, in the prevention of cisplatin induced-hearing loss in rats. LPT99 (50-200 mM in vehicle) was administered by transtympanic surgery in young male Wistar rats. Ototoxicity was induced immediately after by intraperitoneal slow infusion of cisplatin (10 mg/kg). Hearing was evaluated by registering the auditory brainstem response (ABR) to click and pure tones, before and 3 days after cisplatin administration. Finally, rats were euthanized and the cochleae dissected for total RNA extraction and gene expression or histology. LPT99 treatment of rats attenuated the threshold shifts induced by cisplatin after 3 days of its administration when compared to the vehicle-treated rats. Thresholds of tone frequencies of 20, 28 and 40 kHz were significantly lower than in the cisplatin group. This protective effect was dose-dependent, showing 100 μM dose the best profile. In addition, LPT99 diminished the alterations in ABR peak latencies and amplitudes induced by cisplatin administration. The expression of p53, Il1α and Kim-1 was reduced in LPT99-treated cochleae, suggesting that LPT99 prevents inflammation and apoptosis. In conclusion, transtympanic administration of LPT99 protects from cisplatin-induced hearing loss in rats, confirming APAF-1 as a valid pharmacological target and postulating LPT99 as a potential first in class drug candidate.

      Inhibition of APAF-1 with LPT99 prevents cisplatin-induced apoptosis in HEI-OC1 auditory cells
      HEI-OC1 (House Ear Institute - organ of Corti 1) is an epithelial otic cell line that was derived by Kalinec et al. (2003) from the cochlea of a transgenic mouse called ImmortomouseTM, which harbors a temperature-sensitive mutant of the SV40 large T antigen. The modulation of culture conditions allows the progression of the progenitor cells to a differentiated hair cell-like with a phenotype similar to that of the adult organ of Corti. One the most interesting characteristic of these cells is their sensitivity to ototoxic drugs such as aminoglycoside antibiotics or antineoplastic agents as cisplatin, which can cause sensorineural hearing loss. Cisplatin is a highly effective chemotherapeutic agent, but it has significant ototoxic side effects. Apoptosis is an important mechanism of cochlear hair cell loss following exposure to cisplatin. The present study examined the effects of LPT99, a second generation of APAF-1 inhibitors on cisplatin-induced apoptosis. Viability and growth rate of HEI-OC1 cells were determined using a crystal violet based staining method and the activation of Caspase-3, a biochemical marker for apoptosis cell death was evaluated with immunocytochemistry. We observed a dose-dependent decrease in cell viability after challenge with cisplatin (0-5 μg/mL); however survival rate increased in the presence of 1 μM LPT99. According, cells treated with cisplatin showed an IC50 of 4.47±1.94 μg/mL, which increased dramatically to 10.51 ± 3 μg/mL in the presence of LPT99. In addition, immunofluorescence studies suggest that the activity of Caspase-3 after cisplatin treatment decreased in the presence of LPT99. These results suggest that LPT99 protected the cells HEI-OC1 against cisplatin-induced apoptosis by inhibiting of APAF-1.
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    5. 1000

      1000 Member

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      Spiral Therapeutics Begins Phase 1 Trial of Hearing Loss Drug
      Published on December 28, 2018

      Spiral Therapeutics, a clinical stage pharmaceutical company focused on the development of first-in-class therapies targeting inner ear disorders, announced the initiation of its Phase 1 clinical trial of LPT99, the company’s lead investigational drug candidate targeting prevention and treatment of hearing loss.

      Spiral’s Phase 1 clinical trial is being conducted at a single site in Australia and is a randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the safety and tolerability of LPT99 administered to healthy adult subjects. Spiral plans to enroll approximately 32 healthy participants and to complete the study by the second quarter of 2019.

      Spiral Therapeutics recently secured $3.7 millions part of a Series A financing round co-led by Savoir Capital and Camden Partners to continue to advance its hearing loss pipeline. The company, which has reportedly raised over $8.3 million since its incorporation in early 2016, plans to secure additional funds into this round. Spiral’s executive leadership includes industry veterans Eugene de Juan and Justin Hanes, and renowned neurotologist Charles Limb.

      “Initiation of our Phase 1 clinical trial is an important step in Spiral’s mission to bring new and effective drug therapies to a field with large unmet needs,” said Hugo Peris, founder and CEO of Spiral Therapeutics. “This trial also confirms our development capabilities and our understanding of inner ear disorders, and marks Spiral as a leader in the field. We will continue to leverage our core competencies in advancing the development of LPT99 and expanding our pipeline.”

      Dr Charles Limb, Chief Medical Officer of Spiral Therapeutics said, “LPT99 is an exciting drug candidate, which represents a new class of potentially transformative treatment options in the rapidly evolving field of hearing loss therapeutics.”
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    6. Contrast
      No Mood

      Contrast Member Benefactor Hall of Fame

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      This doesn't regenerate hair cells or ribbon synapses or auditory nerve fibers. It just protects hair cells during chemotherapy and ototoxic medicine.

      Literally copying Decibel Therapeutics to a tee.
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    7. Nick47

      Nick47 Member Benefactor

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      Spiral Therapeutics, Inc. ("Spiral"), a clinical-stage company focused on delivering therapies for inner ear disorders, today announced that the Company recently completed an $8.25M financing, with new proceeds that will fund the continuing development of its lead candidate, SPT-2101, for the treatment of inner ear inflammation. Existing investors Savoir Capital and Catalio Capital Management participated in this financing and were joined by Humboldt Fund and other family office investors.

      Spiral Therapeutics Completes $8.25M Financing and Initiates Phase 2 Trial in Ménière's Disease
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    8. Aussie Lea

      Aussie Lea Member

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      Always happy to see ear disorders getting investment.
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    9. GlennS

      GlennS Member Podcast Patron Hall of Fame

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      Only took almost 5 years.
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    10. patorjk
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      patorjk Member Benefactor

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      I mentioned this in the OTO-413 thread, but Spiral Therapeutics is acquiring the rights to several parts of Otonomy's pipeline, including Otividex (the failed Ménière's disease drug), OTO-510 (otoprotectant drug related to Cisplatin), and OTO-413 (hearing/synapses). On their website they mention:

      Continuous drug diffusion across the membrane and into the cochlea 1-3 months​

      Now that Otonomy has failed, part of me wonders if their drug delivery was the problem. They touted extended release, but maybe their formula was the problem. Otividex should have been a slam dunk - it's simply Dexamethasone mixed with Otonomy's extended release gel, and Dexamethasone is already used off-label for Ménière's. If Spiral Therapeutics can improve delivery, they may be able to breath new life into these drugs. I hope they take a close look at OTO-413.
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    11. Artemis2K
      Kick ass

      Artemis2K Member Benefactor

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      I had tinnitus for as long as I can remember. Got bad later.
      What does this mean for clinical trials? Will this be a complete reboot? I really hope the BDNF drug gets through. If it works, then both sides of hearing loss could become treated as long as the hair cell drugs work also, and this could lead to treatments for other problems outside of the ear. BDNF has been proven to be very important for many factors.
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