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Scientists Discover a Cure for the Deadliest Strain of Tuberculosis (nytimes.com)
511 points by rafaelc on Aug 14, 2019 | hide | past | favorite | 43 comments

This advancement is especially promising because access to Delamanid (a drug similar to Pretomanid) is very difficult for patients in many countries. The company that developed Delamanid, Otsuka Pharmaceutical, has been extremely restrictive in allowing access to it.

I know someone critically ill who was petitioning Otsuka for access to Delamanid under compassionate use, but Otsuka would only agree to give access if the patient stayed in a hospital for 4-6 months. This is just a crafty way for pharma companies to refuse access since they know the cost of months of hospital stay is not affordable or practical. Luckily in this instance, TB Alliance and others fought with Otsuka to get this patient access to the drug.

In many high-need countries (India/Africa/China etc), desperate doctors frequently just lie to Otsuka about the patient staying in the hospital in order to get access to the drug.

Opening access to Pretomanid is a great advancement!

Why do they want extended hospital stays? Is it to boost their success statistics or something?

The reason is that in some trials of Delamanid, a rare but serious side effect called QT prolongation was uncovered. To monitor for this side effect, a patient needs to have regular EKGs done. Since Delamanid is not approved in many countries yet (including the US), Otsuka wants to eliminate even the smallest chance of a patient complication which could delay their approval process. So they call for full hospitalization while the patient is on the drug.

For brand new drugs that cure critical illnesses, the FDA has a compassionate use program (officially called Expanded Access) which allows drugs that are not fully approved yet to be used immediately by very ill patients. Otsuka requiring months of hospitalization to monitor for a rare side effect was just wrong and against the spirit of compassionate use access IMO. This side-effect is easily and cheaply monitored by regular EKGs at a local primary care doctor or urgent care clinic.

Considering QT prolongation has resulted in several drugs being pulled off the market, I’m not sure I blame the Pharma company for being cautious.

They are putting the use of the drug entirely in the hands of people who might not have the resources or training needed. If the use of the drug resulted in several deaths, it could significantly delay approval or kill the program entirely.

True that they're being cautious to protect their investment in the drug. In the case of TB, it's taken seriously enough that the drugs used to treat MDR/XDR TB are taken under close medical supervision, especially brand new drugs like Bedaquiline and Delamanid. They are usually administered under DOT (directly observed therapy) where a patient is required by law to take the drugs daily in front of a witness, or with lower-risk patients they use VDOT (Video Directly Observed Therapy) where patients can use an app to video record themselves taking the medicine daily and submit the evidence to the local Department of Health. In cases where patients don't comply to treatment, they can be arrested and isolated due to the public health risk.

Protecting their investment sure, but it can extend beyond that to impact clinical perceptions of the drug such that it limits use unnecessarily (regardless of whether Otsuka markets it).

I was tangentially involved in a clinical development program that offered access through compassionate use. The folks who received the drug were truly out of options. As a result several died. Investigation determine the drug was not the cause. That didn’t stop the rumors from swirling and several physicians pulling out of the clinical trials and actively discouraging patients from taking part. Probably extended the development by at least 2 years (it was eventually approved) and as a result many people who could of benefited from it had to wait, which likely resulted in a number of deaths that could have been avoided.

So QT should be paying for the hospital stay and the drug if they are using this data. Drug trials aren't free either.

Couldn't some sort of waiver be signed in presence of various witnesses and properly notarized etc work in these cases instead? That way the company would not be held liable and the patient, by his own choice, can get access to the drug when he needs it.

That only takes care of liability, not the PR cost of having people die due to a side-effect of your drug.

To make sure TB is cured and avoid developing a new drug-resistant strain?

I'm going to step in here as a reminder that Africa has more than 54 countries.

While you are not wrong, India (1.32B) and China (1.41B) both have larger populations than Africa (1.25B) so it makes sense to to group these together (as regions, not countries)

This is why I refuse to apply to pharma companies for work or war companies.

I think they're unethical and morally bankrupt.

I had a normal TB 3 years back. I was 22 years then. I have forgotten the drug names I took but it was 6 pills per day to be taken at morning with only half glass of water. I took that for 6 months. I am from India so not sure if any advanced country treats normal TB with less number of pills. But what I can say is that taking those pills in daily in empty stomach was unbearable, many times I thought to giveup but the love for my family kept me going. I can't imagine what those people are going through who are taking 40 pills a day. If FDA approved Pretomanid then in my opinion they should take more people into the trial.

You must have taken the standard RIPE therapy which consists of 4 powerful drugs: rifampin, isoniazid, pyrazinamide, and ethambutol. Plus sometimes doctors add some other pills to control specific side effects a patient may be having like nausea or dizziness.

I really appreciate you adding your personal perspective. A big problem in TB today is that the “western” world sees it mostly as a “not-my-problem” kind of disease. What people forget is that TB is airborne and that the world is getting smaller. It will start impacting everyone.

TB is everyone’s problem and more investment should be made by the wealthier countries toward it’s care.

https://www.nature.com/articles/d41586-019-02464-0 is the Nature article for those that don't want to bother getting passed the NYT's registration.

It's not a drug discovery, it's an FDA approval of a 3 drug combination treatment of existing molecules. It's not a more deadly strain of tuberculosis, per se (to clarify: as in "more virulent", like H5N1 is compared to normally circulating strains of influenza), but it's the "XDR" designation. This is regular tuberculosis that has developed drug resistance to the prior final lines of treatments.

edit: pretomanid is the newest and most novel of the 3 drug treatment. The FDA release is useful: https://www.fda.gov/news-events/press-announcements/fda-appr...

Pretomanid was approved by the FDA today. Obviously the molecule and treatment protocol has been in design and study for years up to this point, but FDA approval is a reasonable endpoint to celebrate as a "cure being discovered."

I suppose you could also argue it's "not a cure" because in the small trail performed it only cures 90%.

Finally, I don't know what you're getting at with "not a more deadly strain". XDR TB is "eXtensively Drug Resistant" which makes it also the most fatal form of TB. There are a lot of things which left untreated can kill you. I assume it is normal for fatality rates of a strain of disease to be stated as the post-treatment fatality rate.

True, but the article says deadliest, not deadly. If my sister is the deadliest she's ever been, that doesn't mean she's going to kill me or even that she's even going to try. She might simply be more angry than ever before, and so the likelihood of killing me while still extremely low is higher than previous.

Clickbaity, yes. Accurate, hard to say.

I think it is fair to say that using the term "deadliest" in this context gives almost everyone the impression that this strain of the disease is indeed deadly (that is to say, that a fair number of people die from it).

So if very few people die from this strain (and I don't know the answer to that, but the grandparent comment implies that very few do), then I'd say it is definitely not accurate.

Tb in general is surprisingly deadly actually.

[0] "The World Health Organization estimates that 1.8 billion people—close to one quarter of the world's population—are infected with Mycobacterium tuberculosis (M.tb), the bacteria that causes TB. Last year, 10 million fell ill from TB and 1.6 million died." ... "There is growing resistance to available drugs, which means the disease is becoming more deadly and difficult to treat. There were 558,000 cases of drug resistant TB last year."

[0] - https://www.tballiance.org/why-new-tb-drugs/global-pandemic

EDIT: I say surprisingly, because before recently I was under impression that tb, being bacterial infection, was solved long ago.

Yeah, I knew that TB overall was deadly - but the post I was referring to implied that this particular strain was not deadly. As I said, I don't know if the implication about this strain is correct, but if it is then referring to that strain as "the deadliest strain of Tuberculosis" would be inaccurate.

TB generally, and XDR TB specifically, are quite dangerous on a global scale.

"By the end of 2016, XDR-TB has been reported by 123 WHO Member States. Information from countries with reliable data suggests that about 6.2% of MDR-TB cases worldwide have XDR-TB.

In 2016, there were an estimated 490 000 new cases of MDR-TB worldwide. Only a small proportion of the XDR-TB cases among them are detected given that many low and lower middle-income countries still lack sufficient diagnostic capacity to test for resistance to second-line drugs and thus detect XDR-TB."

In a study in South Africa, MDR-TB had a case fatality rate of about 9% in HIV- individuals, and 20% in HIV+ individuals.

Yeah, won't repeat it here, but see my response to "UnFleshedOne" in this thread.

Hold on, before we get in to a confusing argument of terms, does this strain of tuberculosis have one of highest mortality rates per infection or not?

If so, the headline is more or less accurate.

If not, please explain.

Apologies for the Elsevier link, but https://www.thelancet.com/journals/lanres/article/PIIS2213-2...

The report estimates around 40% mortality for MDR-TB and 60% mortality for XDR-TB.

This compares with https://www.who.int/gho/tb/epidemic/cases_deaths/en/ which gives about ~13% mortality for all TB cases world wide.

So, I think the headline is accurate about that. However, we could cure (at least for some definition of "cure") XDR-TB before; it just took an incredible amount of time with some terrible drugs and some individuals still relapsed. Pa could be a game changer, though. I'll give it a "somewhat justifiably clickbaity" rating. ;)

Approved by the FDA today, this is a 3-drug cocktail which has shown a 90% cure rate against a highly deadly strain of TB called "XDR" (eXtensively Drug Resistant) in a small trail of 109 patients. It consists of pretomanid, bedaquiline, and linezolid, dosed daily for 6 months.

Pretomanid was developed by the TB Alliance, and is targeted to be offered at a cost of $1 per dose. Back in 2000, apparently they raised about ~$150 million for drug development [1], I'm curious how much more they raised/spent since then to get to this point.

Bedaquiline was developed by Janssen, it's not clear at what cost. They have a tiered pricing structure for a 6-month course ($900/$3,000/$30,000) but 3rd world cost has recently come down to $360. [2]

Linezolid was developed by Pfizer, off patent since 2015. Pfizer doesn't seem to limit the cost in South Africa to any reasonable extent, charging between $60 - $150 per dose depending on who is buying it. However at least generics have come online in pill form for ~$7/dose [3]

It sure would be nice if the development costs from Janssen and Pfizer were public, since it makes it basically impossible to compare, but the development model for pretomanid, and the innovative funding of the trials through TB Alliance to me demonstrates -- at least for diseases which are prevalent enough to build these alliances and obtain the donations -- a truly superior approach to providing treatment options for the world at prices that the world can afford.

Congratulations to everyone involved for reaching such an impressive outcome, and particularly for doing it in an ethically responsible and economical approach. XDR TB is not currently extremely prevalent (seems like < 5% of all TB, but growing), but this is the first new TB drug approved in apparently in 40 years, and changes a 60% fatal diagnosis into a 90% curable disease, with a much simpler treatment protocol.

[1] - https://www.tballiance.org/news/public-private-partnership-a...

[2] - http://www.treatmentactiongroup.org/sites/default/files/real...

[3] - http://www.treatmentactiongroup.org/tb/linezolid-factsheet

Firstly Ebola then tuberculosis, this week has been fascinating in the medecine world!

There was also a Chlamydia breakthrough. Good week indeed!

That's absolutely amazing. According to my GP, there is a LOT of it here in Melbourne, Australia. Many of the strains are becoming antibiotic-resistant, so this is quite big news!

Was this separate from the Chlamydia vaccination passing a safety trial?


Nope. Thats the one. I guess less of a breakthrough and more of a promising step towards a treatment!

I'm treating an XDR-TB patient right now (fortunately doing well). Too bad this wasn't there when we started.

What would be the ramifications of switching from current treatment to the new one midway through the current treatment?

Well, I don't have a supplier for this medication currently, and a study size of 109 is not large. The results are very promising but with TB, only certain medications work in certain combinations and you don't get to find out if you treated it wrong until sometimes years later when they relapse.

If this particular patient asks about this study, and I won't be at all surprised if they do because this is a major article in a major paper and they're pretty well informed about their condition, I would probably tell them that while it looks very compelling I don't want to do this incorrectly and right now the best evidence is the WHO guideline as currently followed. Without going into detail, this patient is already on two of the three meds as it is.

I think they mean started in terms of treating patients with TB, as a physician rather than this particular patient? But maybe you’re right in which case I’d guess they’d be out cured much sooner.

Great news. I have not followed this, can you tell if it looks like this be any less susceptible resistance development?

Couldn't say definitively, but given that the biggest risks for resistance are monotherapy and intermittent therapy, shorter, less complex courses help to reduce the effective occurrence of both. Currently my MDR and XDR patients have about an 18+ month time frame; slashing the treatment time potentially to a third is a huge win, and we have robust directly-observed therapy infrastructure to ensure doses are actually taken. Unfortunately this last is not guaranteed in the developing world.

Why does it take so long to treat TB, out of curiosity? 6 months is crazy long, isn't it?

The article covers that, in brief:

Tuberculosis germs burrow deep into the lungs and barricade themselves inside clumps of dead cells. Breaking those nodules apart and killing all the bacteria inside requires taking drugs for months.

What about epimerox? Where is it? https://en.wikipedia.org/wiki/Epimerox

This comes as a great news to many developing countries where doctors are worried about TB strains which are difficult to cure. TB carries with it the potential for great damage to lungs. People who suffer from TB have severely diminished breathing capacity and for many the 5 year prognosis is not good.

Scientists are on fire :)

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