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Re: OCUL, sustained release prostaglandin. In the beagle study for Durysta (Allergan’s approved version), they compared tissue concentrations for topical v. sustained released for various tissues, and for the cornea, the ratio was not as high as for the iris-cilliary body but still astronomical — about 1000x. https://www.liebertpub.com/doi/epdf/10.1089/jop.2018.0067
But I don’t understand the clinical significance of this. For example, one side effect of topical prostaglandin drops is a change in iris color, estimated to occur in at least 10%, maybe 20%, of patients. See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1771317/
In the Durysta phase 3, they reported iris color change in less than 3% of patients, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602154/, yet the concentration of the drug in the iris is 4400x. So clearly side effects don’t necessarily follow from an increase in concentration.
Prostaglandins are strange drugs. E.g., dosing is once daily and studies show that twice daily dosing can be worse than ineffective, it may result in reduced efficacy.
You would think that this is something OCUL management would have considered. But I certainly don’t know for sure and they might just figure it’s worth a try.
I see your point, I don’t know what concentration is reached at the cornea and 26 micrograms of active ingredient sounds small but it’s roughly the size of an eyedrop. (I know this as I instill my glaucoma meds with a micropipette set at 12 mcg). And a bimatoprost eyedrop is .03% active ingredient, so 26 mcg is about 900 x the active ingredient in one drop. Of course, it’s released over about 180 days.
At the same time, if the concentration is so high, why was the lower dose in the trial ineffective?
From an article reporting on Durysta phase 3 trial safety results:
Iwfal’s point is that Durysta didn’t show endothelial loss at 6 months either. See the discussion on endothelial loss in the results section of the article cited below, very small separation of the curves, and only towards the end.
On the other hand, Durysta doesn’t seems to be fully absorbed, see this discussion, so that might explain why repeated dosing is problematic:
Implants were typically observed to initially swell as they biodegraded, and the majority of those received at the first administration visit (day 1) were estimated by the investigator to be 76–125% of their initial size at assessments through month 6. By 12 months, the majority of those implants had either totally biodegraded (n?=?6) or were estimated to be ≤?25% of their initial size (n?=?26). At month 24, a total of 34 patients were evaluated with gonioscopy, and the implant administered on day 1 had biodegraded and was no longer visible in 26.5% (9/34) of these patients. Of all implants administered on day 1 (including two implants per study eye for the 20-µg dose strength), 30 implants (in 25 eyes) were still visible at month 24. Size assessment was missing for 6.7% (2/30) of these implants; of those assessed, the implant size was estimated to be ≤?25% of initial size for 75.0% (21/28) of the implants and 26–50% of initial size for 25.0% (7/28) of the implants. Analysis of residual implant at month 24 was limited to assessments for patients who did not meet criteria of total implant biodegradation allowing early study completion (at or after month 18
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007425/
Re: Ocular Therapeutix Paxtrava. Here’s a link to the presentation. Efficacy looks good, not so sure about the side effects. https://investors.ocutx.com/static-files/7d4551c6-1158-4a4b-a13a-2198a210de00
Re: Verve. It would be pretty misleading -- one might say Fibrogenic -- to tout the second generation LNP as expected to solve the problem if they saw they same liver effects preclinically. He did say that it was "well tolerated at therapeutic doses" in the 75 patients exposed in third party testing. I thought it was pretty clearly implied that Verve added the "proprietary" GALNAc targeting moetity to what was licensed -- if it's proprietary to Verve, it wouldn't be something the third party licensed, would it? Also, Kathiresan used the word "added" a couple times, which I took to mean, added to what was licensed.
Still, even though Kathiresan is touting the GALNAC as a reason he expects the second generation to solve this issue, there is always the possibility that adding it the LNP will create a problem not present in the 75 people who were tested.
I bought a few shares, it's beaten down and I have a close relative with likely FH (albeit response to moderate statin treatment), so I want to root for this to work.
Re Verve: Good interview of Verve CEO, attributes safety issues in dose escalation trial of gene therapy/PCSK9 inhibition trial to lipid nanoparticle delivery system, believes second generation system will avoid the problem.
Stock fell from 14 to 8 on news, recovered a bit today.
https://www.biotechtv.com/post/verve-therapeutics-april-2-2024
Re: IIHS.org rating of ADAS systems
This just tests how intrusive a nanny the system is, not whether it actually steers the car and brakes and maintains speed appropriately. They would apparently give high marks to a system that shocks your private parts if your attention wanders but and occasionally drives off the road into a tree for amusement.
Re: Athyrium debt. So far as I can tell, the third tranche -- unlike the first two tranches -- is uncommitted, so, yes, they needed to satisfy the market. The 10-K uses that word to describe it, indeed the definition of Third Tranche is:
AI drug developer Exscientia down about 17% after firing CEO for engaging in relationships with two employees, and the Chairman of the Board for covering it up. https://investorshub.advfn.com/Biotech-Values-1418
The filing implies that the relationships were sequential, not simultaneous; this is highly inefficient and understandably grounds for dismissal at a firm on the leading edge of AI. No good sentient robot would do that.
Re: Injector pricing. This injector says:
This Sunday session should interesting:
I see the point when running a large trial v placebo. But running a 1000 or 2000 patient noninferiority trial v a drug with lots of side effects selling 1 million prescriptions a month— how hard is that to enroll? Who cares about seasonality? Seems to me that’s the least of ENTA’s problems.
Re: ENTA
If anyone cares, the Morgan Stanley change to the target price is based on this analysis:
You're citing results from a retrospective observational study based on data that's a year or more old. Not exactly out of date, but we are two boosters beyond that and lots more infections as well. And different strains. So who knows that the current death rate is.
In any event, if you believe the Jama study, what trial is Enanta going to run? 235 v. Paxlovid in high risk 65 and over? In that population, per the article:
Re: EV repairs
Tesla will soon be offering “Full Auto-Destruct Mode,” where sensors will detect damage to the car, and if estimated repair costs exceed an amount randomly chosen by Tesla, the car will self-destruct. The feature has been previewed in a number of cars, which have spontaneously ignited.
Presumably at some point insurance rates will reflect exorbitant repair costs or the cars will become uninsurable.
I understand that dysphagia is a reasonably common and serious side effect when Botox is used to treat cervical dystonia — and, notably, Daxxify rates of said side effect are substantially lower. But the question Marthambles asked is:
“Dysphasia” — I will bet an insubstantial amount of money- say the value of a RVNC share - that dysphasia is a wild spell correct for “dispersion” - the lack thereof presenting an issue. Soma2022 had a fine post outlining his technique for dealing with the frontalis.
There’s only one person who knows for sure but I interpreted to mean something else — like with all that debt, they might be toast in a downturn.
Agreed. 275 was a typo, my $14,750 number was correct. So you agree, then, that for an investment of $14,750, a practice gets a discount of about 30%. So the $41,250 investment you mention, larger than most practices would invest, is not necessary to get a very large discount.
Re WSJ.
Click the comment box closed and scroll to the top, you get the editorial “ The Harassment of Elon Musk
The Tesla CEO faces a remarkable number of government probes.” It goes through the large number of Musk probes.
Re: Paxlovid
As you know, the new data is based on retrospective observational data, not a randomized study, so there's lots of possible confounders. Still, it appears to me that the criteria the new study used for "high risk" is rather stricter than the relatively loose definition in the EPIC-HR trial (the one that showed 88% relative improvement).
In the EPIC-HR study (reported at https://www.nejm.org/doi/10.1056/NEJMoa2118542?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed) a BMI of at least 25 is sufficient to qualify as high risk, so is achieving the ripe old age of 60.
In the Cleveland Clinic observational study (see e-table 1 in the supplement), they require rather more heft, a BMI of 30 or more. As to age, I didn't even see that as an explicit risk factor but they do refer to NIH guidelines, which refer to age 65 or greater as high risk.
Bottom line, so far as I can tell, the new study shows reduced efficacy in a significantly more restricted population.
And speaking of Paxlovid in patients that are not high risk, the results of the EPIC-SR study were posted on clinicaltrials.gov, at https://www.clinicaltrials.gov/study/NCT05011513?term=EPIC-SR&cond=Covid19&rank=1&tab=results. Not sure if they were reported via press release or in the media; I saw it one of the many Vinay Prasad anti-Pfizer/Paxlovid screeds. The results are basically, no benefit. E.g., 1. TIME TO SUSTAINED ALLEVIATION OF OVERALL COVID-19 SIGNS AND SYMPTOMS THROUGH DAY 28, Paxlovid arm, median 12 days (11-13), placebo arm, 13 days (12-14).
So yes, there definitely seems to be room for more efficacious drugs.
I'm of the view that CosmeticMD is, in fact, an exterminator. Why? I can't be sure but he writes this:
Re: Pricing strategy. I'm not entirely sure what to think. On the one hand, I am reminded of this famous scene in Dr. Strangelove, 2 minutes into this clip
There must be an easy answer to this obvious question, but how do you price Daxxify at $420 for CD while discounting 30% or so under that for 50 vials in esthetic? Neurologists can’t purchase? Or maybe they don’t care, it’s really what the insurer will pay and they get good value at 420.
Re: Daxxi Lite. Here’s another.
https://dr-ruth-penton-polson.square.site/
And another