Spiral Therapeutics

Spiral Therapeutics Receives Positive IND Submission Guidance from FDA

LPT99 is currently being tested for the treatment of other hearing loss indications, including noise-induced hearing loss and age-related hearing loss. Clinical trials for LPT99 will begin in early 2018.

http://www.prnewswire.com/news-rele...d-submission-guidance-from-fda-300524868.html

 

Any papers on that?

 

I think this one: Inhibition of APAF-1 with LPT99 prevents cisplatin-induced hearing loss. I can't find it anywhere, though.

 

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

https://www.tinnitustalk.com/posts/241986
https://www.tinnitustalk.com/posts/241988

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.

Title:
Inhibition of APAF-1 with LPT99 prevents cisplatin-induced hearing loss
Abstract:
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.
(https://webcache.googleusercontent....handle/10261/154222+&cd=8&hl=en&ct=clnk&gl=us)

Title:
Inhibition of APAF-1 with LPT99 prevents cisplatin-induced apoptosis in HEI-OC1 auditory cells
Abstract:
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.
(https://webcache.googleusercontent....andle/10261/154180+&cd=13&hl=en&ct=clnk&gl=us)

 

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.”

 

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.

 

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

 

Always happy to see ear disorders getting investment.

 

Only took almost 5 years.

 

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.

 

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.

 

→ Here's a Twitter response to Frequency Therapeutics' failure from Hugo Peris, CEO of Spiral Therapeutics. Let the next biotech PR machine step up.

I will urge all members to steer clear, learn and set the bar higher.

As an investor, what proof would we want?

For me:

1. A human trial showing clinically significant improvements in audiogram of >10 dB on at least 2 frequencies at 2 separate time points in at least 30% of patients.
2. No speech-in-noise bollocks or word recognition in 10% of participants. If you market it as hearing restoration, then an audiogram is fine by me.
3. No silly images created on computers, or mouse or rat ears.
4. We need to really lift the bar. If the bar is high, then would-be failures drown early and we don't get fleeced.

 

And if I might add: the hearing improvement must last long term. Some FX-322 patients lost their ‘gains’ after 1/2 years. Either the hair cell is there, or it isn’t there. Hearing loss drugs that need to be repeated yearly, hoping it will have the same effect as last time, is just ridiculous.

 

This is one thing I'm worried about. I have no idea how fragile those new hair cells would be. Would they have the myelin sheath meant to protect them? Would the hair cells actually be durable enough in the regeneration process?

What if Frequency Therapeutics also wasn't strict enough in their clinical trials and the patients needed to be in something like the world's most quiet room in the process? During prenatal development, how much hearing protection do fetuses have within the womb, and how vital could that be for adult regeneration?

 

I'll happily spend 9 months in a bubble, reading. Just give me the shot.

 

This is a great question and something I didn’t think of. This would be easy to do if someone suffers from reactive tinnitus or hyperacusis from lower noise levels.

For normal people, maybe all you need to do after getting a dose of OTO-413 is wear earplugs if noise levels reach 70 dB or more.

But who knows.

 

Sorry, but I had to.

 

The womb is a very noisy place actually.

 

Here are the list of patents that Spiral Therapeutics currently have.

If you want the link about their delivery method, here it is.

I don’t see how using polymer would make a difference in getting the drug into the round window instead of missing it but maybe someone like @Nick47 could explain how it might be possible.

 

It doesn't, delivery still has to be accurate.

Imagine a pot of spaghetti. Each strand of spaghetti is a polymer chain. They’re entwined, but entirely separate strands that can be pulled apart easily.

Now you pour in a bottle of glue. The strands are now stuck together and form one giant network. No single strand can be separated without you injecting energy into the system by having to physically pull a strand apart from the rest.

This is what a crosslink is. It stabilises polymers into one network which makes them more robust and long lasting. It’s a very routine way of drug delivery on medical devices.

If we inject the drug into the ear with no crosslinked network, all of the sites for cell activation may be saturated and only 50% of the drug has been used. Some of those cells may not ‘take’ and form a new hair cell for whatever reason. The remaining unused drug is metabolised by the body and is basically waste.

Now, if we do the same with a crosslinked polymer gel. It releases the drug much slower - a timed release. This means a slow and steady stream of the drug is constantly available to any hair cell sites. If a site doesn’t take on day 1, maybe the drug release on day 2 will have more luck.

The polymer breaks down slowly with enzymatic action, hydrolysis and heat within the body and is eventually metabolised.

This gives you several days or weeks of drug release.

 

In honesty I don't know the chemistry of these delivery compounds.

I've completely switched off from all regeneration treatments as they are so far away now.

The idea of natural regeneration was magical thinking at this stage. Technology is miles ahead. Optical light cochlear implants in less than 10 years. Implants done by robots where most residual hearing is retained by the availability of otoprotective drugs. Hey, they are even working on vestibular implants.

Ultimately the regeneration treatments didn't work, no matter how you delivered them.

 

Vestibular implants? Optical light chochlear implants? Wow, never heard of this but it sounds cool.

Spiral Therapeutics may have something here but, as you said, it's so far away now.

 

Could Spiral Therapeutics be granted the same fast track designation for their hearing loss products as Frequency Therapeutics? I'm not sure how exactly this process works and what the requirements are.

 

I think they should be able to receive Fast Track designation as Otonomy had completed OTO-413 Phase 1 and 2A at the 0.3 mg dose with success and since Spiral Therapeutics bought OTO-413. It depends on whether they continue with the current delivery method or start back from Phase 1 with the new delivery method.

I wonder if it’s possible for the FDA to allow them to use the new delivery method in the Phase 2b trial instead of having to start from Phase 1. If they can’t, maybe with the Phase 1 trial they could recruit at least 100 patients and if that’s successful, maybe the FDA will allow them to go straight to Phase 3 but allow them to sell OTO-413 out in the market at the same time.