In a Phase III trial, Proxalutamide reduced mortality of Covid patients | Hacker News Reader

In a Phase III trial, Proxalutamide reduced mortality of Covid patients

europeanpharmaceuticalreview.com

60 pointshu330 comments

> there were 141 deaths in the control arm, a 47.6 percent mortality rate

That seems very high to me. I checked quickly for data, and I found a study[0] showing mortality rates for hospitalized covid patients in the U.S. between from 9% to 15%.

So where did they find a control group with 47.6% mortality? Is care that much worse in Brazil vs. the U.S? Are they only giving this to mortally ill patients? The claim of 92% efficacy depends on this very high control group mortality.

[0]: https://jamanetwork.com/journals/jamainternalmedicine/fullar...

>So where did they find a control group with 47.6% mortality? Is care that much worse in Brazil vs. the U.S?

Yeah, unfortunately it is -- 38% according to this news piece, 80% for ICU patients[1]. It makes sense that it is even higher in Amazonas, the Brazilian state reported in the study. Over there they had a very serious health system collapse the last few months; even oxygen supplies were completely depleted statewide for a couple of weeks.

[1] "Mortality in hospital patients admitted with Covid in Brazil is one of the world's largest" https://saude.estadao.com.br/noticias/geral,mortalidade-por-...

It doesn't help that a very aggressive strain of covid was discovered in that region of Brazil:

> P.1 infections can produce nearly 10 times more viral load than in other COVID-19-infected persons

https://en.wikipedia.org/wiki/Lineage_P.1

I think it's going to depend very much on the distribution of patients with the different WHO Covid Ordinal Scale categories within the cohorts.

If there were a lot more 5s (severely ill hospitalised patient on non-invasive ventilation or high-flow oxygen) vs. 3s (hospitalised patients not needing oxygen therapy), it would presumably make a large difference.

I've been trying to find this stat for the whole pandemic. To what degree are our medical systems reducing mortality rates?

I believe the trial data is from summer 2020? Survival rates of hospitalized patients improved dramatically over time.

Might be red herring: https://twitter.com/schneiderleonid/status/13721485262396006...

Good they actually have some understanding of the underlying mechanism. Also this is an oral drug! It reduced mortality risk by 92%: https://www.europeanpharmaceuticalreview.com/news/147167/pro...

Summarizing, it looks like the TMPRSS2 protein is necessary for the virus to replicate, and the Androgen Receptor modulates its transcription.

But where I'm confused is why this drug in particular was studied, instead of an approved AR antagonist like bicalutamide or enzalutamide. Way easier to dispense those than some clinical trial drug, right? And is it important that the drug is a silent antagonist of AR rather than an inverse agonist?

Also, how does this affect women? Are we at less risk of mortality through this mechanism? My T levels are very low, but all of us have androgens and their receptors. Maybe TMPRSS2 gets transcribed even when T or DHT levels are low?

All good questions. See the sibling comment that it may be too good to be true https://news.ycombinator.com/item?id=26517243

I've changed the URL above to that one from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899267/, which has the paper.

Generally with specialized papers we've found that it's best to link to the best third-party article and then have a link to the paper in the thread. Unfortunately the third party article often isn't great, but it's at least an easier place to get some context, and we can replace the URL when people point out a better one.

I appreciate it. Hopefully the trials can confirm this drug as another tool against covid.

> Also this is an oral drug!

Asking as a layman:

Would that be a problem for patients who are unconscious or with breathing tubes?

You can always crush the pill and put it into the feeding tube.

This is great news and an amazingly strong outcome! Proxalutamide is an antiandrogen, which reduces some of the effects of androgens including testosterone, so I wonder if this has a stronger effect in males than in females. Although the paper mentions the sex distribution of the patients, it doesn't seem to mention the details necessary to conclude this, but unless I'm mistaken over something trivial I'm unsure as to why. Anyone have any thoughts?

This is an antiandrogen. Androgens are thought to play a role in COVID, and apparently there is a "high prevalence of androgenic alopecia in hospitalized patients with COVID-19".

Also callled "male-pattern baldness" but affects both sexes.

More information here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557269/

> Previously, we have reported that men affected by androgenetic alopecia (AGA) are overrepresented in severe coronavirus disease 2019 (COVID-19).

That’s very interesting. Never read that anywhere else.

> 171 were randomized to the Proxalutamide arm and 65 were in the placebo group.

Maybe I'm missing something but, how does that happen? I'd expect a 50/50 split

What split is optimal depends on what effect size you expect. If you expect a very large effect, you get more statistical confidence from allocating more subjects to the treatment group.

On the other hand, if your treatment is very costly, adding subjects to the control group may be an effective way to increase study power without as much increase in study cost.

(Intuitively, I'm not an expert) Apart from the statistical reasons already mentioned, there is also an ethical one. If you expect the study to confirm the treatment to be highly beneficial, you prefer not to withhold it from your patients.

Trials are often run with multiple arms.

It's not treatement/placebo.

It might be 50mg/20mg/10mg/placebo.

Somewhat unintuitively the statistics in trials don’t require a 50/50 split.

Here is an extreme example: suppose you are an HIV skeptic who believes that AIDS is not caused by the HIV virus but rather by drugs [1]. How large a study would you need to falsify your hypothesis?

Answer: one HIV-positive subject, left untreated, would be enough, if that person were otherwise healthy. If that person died of AIDS, that would leave one of two possibilities:

1. HIV causes AIDS, or

2. Something else causes AIDS and that person JUST HAPPENED to have that other causal factor AND a (harmless) HIV infection.

The odds of #2 are low (because AIDS and HIV infections are both uncommon) so that just leaves the first possibility.

As a side-note, that experiment was actually done by an HIV skeptic, on both herself and her unfortunate daughter [2]. Needless to say, both are now dead.

[1] http://duesberg.com/

[2] https://en.wikipedia.org/wiki/Christine_Maggiore

The company behind the drug tripled their market cap between November 2020 and March 2021. It's now at 11B HKD: Kintor Pharmaceutical (9939 HK).

I wonder what the cost is...the drug appears to be almost brand new.

Medications for people with rare conditions tend to be astronomically priced (attempting to recover r&d costs from few buyers?). Covid doesn’t seem to be particularly rare

The original purpose of the drug was for prostate and breast cancer.

I guess the need is so much more at this point that the cost of producing the drug matters much more. Anyways, it can't be too expensive to produce to be practical, because the valuation of the company increased by billions of dollars.

There are two things that matter in setting the price:

- how much the company needs to be able to make the drugs and turn a profit

- what the buyer is willing to pay

People buying drugs don’t have the choices people have in a free market and these companies know it.

makes you wonder why you couldn't just use bicalutamide which is super cheap relatively.

Reply on news.ycombinator.com