4 ms·

While it is sad that this drug cannot continue for MS directly, I love that this is science work at its best. Experimental drug, through the efforts of termina

While it is sad that this drug cannot continue for MS directly, I love that this is science work at its best. Experimental drug, through the efforts of terminally ill, are able to discover/show/validate quite powerful benefits, but the drug is too dangerous to use itself. So we stop it. It is progress and many times, progress is not easy nor cost free. Thank you to all those who, even in their terminally ill state, helped progress treatments for others.

derefr 6y ago
One thing I’ve always wondered is: how many drugs have we rejected like this, which were actually bimodal in their safety profile, the way many drugs are bimodal (or polymodal) in their effect profile. I.e., that there’s some inherent difference between the people the drug harms, and the people it doesn’t; and if you can identify that difference, and test for it, then you can safely give the drug to only the people it doesn’t harm. The way we currently investigate drug safety in clinical trials doesn’t really allow for this approach. We only seem to do it when a drug is initially declared as safe; introduced into the market; and then we find that it has side-effects that clearly correspond to some subpopulation.
- roganartu 6y ago
  > We only seem to do it when a drug is initially declared as safe; introduced into the market; and then we find that it has side-effects that clearly correspond to some subpopulation. This exact thing happened with another MS drug: natalizumab[0]. It was originally approved in 2004, but later withdrawn in 2005 due to some cases of Progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection that is often fatal. The manufacturer later identified a specific antibody for a virus (JC Virus[1]) present in ~50% of the population which correlated highly with incidence of PML after 1-2 years on natalizumab (~1% chance of PML vs ~0.01% of the normal population). tl;dr the blood-brain barrier maintained by natalizumab also prevents the body from killing the JC Virus in your brain, causing inflammation and eventually death or serious permanent disability. It was then reintroduced but now patients must undertake regular blood screening (every 6 months) for JCV antibodies, and regular (~12 months) MRI scans to monitor for inflammation (though this is pretty standard with MS these days to look for changes in lesions). My wife has a rare type of MS (tumefactive MS, ~3000 people in the US have it) and has been on natalizumab since diagnosis about 3.5 years ago with no evidence of disease progression. The story would've been wildly different if we were born 20 years earlier before these treatments came about, it's honestly amazing. Without modern treatments it's very possible she would've been confined to a wheelchair within 10 years of diagnosis, but instead her symptoms are only really noticeable upon examination by a neurologist. [0]: https://en.wikipedia.org/wiki/Natalizumab https://en.wikipedia.org/wiki/Natalizumab [1]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128336/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128336/
  - BrandoElFollito 6y ago
    My wife was in the same situation as yours and was under Tysabri for many years (10 I think). Then she got the JC virus and had to stop (she was given a choice but decided to stop). She moved to Gylenia and so far so good (or at least as good as someone can be with MS). When she was diagnosed 12 years ago it was the beginning of "modern" MS treatments. 10 years back and it would have been disastrous. In 10 years there may be wonderful advancements. I feel that 100-12 years ago was a true milestone.
- PragmaticPulp 6y ago
  In this case, adverse effects from Bexarotene are virtually guaranteed, even at low doses. This study explored hypothyroidism in even low-dose Bexarotene and found 61 out of 66 patients exhibited hypothyroidism: https://pubmed.ncbi.nlm.nih.gov/30903705/ https://pubmed.ncbi.nlm.nih.gov/30903705/ Bexarotene also significantly elevates cholesterol markers and blood lipids, which would accelerate heart disease and shorten lifespan. The researchers aren’t simply dismissing drugs at the first sign of side effects. We have many drugs on the market with significant contraindications due to adverse side effects in specific populations, and doctors are generally well-informed about testing for these conditions and selecting only suitable drug candidates.
- DanBC 6y ago
  One of the things not mentioned about bexarotene is that it's very teratogenic. That makes it more difficult (but not impossible) to use it for women. > Materials to support the Pregnancy Prevention Programme in women and girls of childbearing potential taking oral acitretin, alitretinoin, or isotretinoin have been updated. Oral tretinoin and bexarotene do not have a Pregnancy Prevention Programme in light of their oncology indication and specialist care setting. However, healthcare professionals are advised that these medicines are extremely teratogenic and product information should be consulted for contraceptive and pregnancy testing requirements when used in females of childbearing potential. When used for cancer these side effects are very common (greater than 1 in 10) or common (between 1 in 10 and 1 in 100). Some of these are going to be mild and temporary. But some of them are serious. > Alopecia; anaemia; appetite decreased; arthralgia; asthenia; chills; constipation; deafness; diarrhoea; dizziness; dry eye; dry mouth; dyslipidaemia; eye disorders; gastrointestinal discomfort; gastrointestinal disorders; headaches; hyperhidrosis; hypersensitivity; hypoproteinaemia; hypothyroidism; increased risk of infection; insomnia; leucopenia; lymphadenopathy; muscle complaints; nausea; oedema; oral disorders; pain; pseudolymphoma; sensation abnormal; skin nodule; skin reactions; skin ulcer; thyroid disorder; vomiting; weight changes
PragmaticPulp 6y ago
The drug used in this study, Bexarotene, is already approved for cancer treatment and available in the United States and Europe. Using Bexarotene in cancer patients makes sense because the side effects are more tolerable than dying from cancer. Using Bexarotene in Multiple Sclerosis patients doesn’t make sense if the net effect is a worsened quality of life (significant thyroid disease) and a shortened lifespan due to accelerated heart disease (hyperlipidaemia and hypercholesterolaemia).
- deleted 6y ago
  [deleted]

derefr 6y ago

One thing I’ve always wondered is: how many drugs have we rejected like this, which were actually bimodal in their safety profile, the way many drugs are bimodal (or polymodal) in their effect profile. I.e., that there’s some inherent difference between the people the drug harms, and the people it doesn’t; and if you can identify that difference, and test for it, then you can safely give the drug to only the people it doesn’t harm. The way we currently investigate drug safety in clinical trials doesn’t really allow for this approach. We only seem to do it when a drug is initially declared as safe; introduced into the market; and then we find that it has side-effects that clearly correspond to some subpopulation.

roganartu 6y ago
> We only seem to do it when a drug is initially declared as safe; introduced into the market; and then we find that it has side-effects that clearly correspond to some subpopulation. This exact thing happened with another MS drug: natalizumab[0]. It was originally approved in 2004, but later withdrawn in 2005 due to some cases of Progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection that is often fatal. The manufacturer later identified a specific antibody for a virus (JC Virus[1]) present in ~50% of the population which correlated highly with incidence of PML after 1-2 years on natalizumab (~1% chance of PML vs ~0.01% of the normal population). tl;dr the blood-brain barrier maintained by natalizumab also prevents the body from killing the JC Virus in your brain, causing inflammation and eventually death or serious permanent disability. It was then reintroduced but now patients must undertake regular blood screening (every 6 months) for JCV antibodies, and regular (~12 months) MRI scans to monitor for inflammation (though this is pretty standard with MS these days to look for changes in lesions). My wife has a rare type of MS (tumefactive MS, ~3000 people in the US have it) and has been on natalizumab since diagnosis about 3.5 years ago with no evidence of disease progression. The story would've been wildly different if we were born 20 years earlier before these treatments came about, it's honestly amazing. Without modern treatments it's very possible she would've been confined to a wheelchair within 10 years of diagnosis, but instead her symptoms are only really noticeable upon examination by a neurologist. [0]: https://en.wikipedia.org/wiki/Natalizumab https://en.wikipedia.org/wiki/Natalizumab [1]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128336/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128336/
- BrandoElFollito 6y ago
  My wife was in the same situation as yours and was under Tysabri for many years (10 I think). Then she got the JC virus and had to stop (she was given a choice but decided to stop). She moved to Gylenia and so far so good (or at least as good as someone can be with MS). When she was diagnosed 12 years ago it was the beginning of "modern" MS treatments. 10 years back and it would have been disastrous. In 10 years there may be wonderful advancements. I feel that 100-12 years ago was a true milestone.
PragmaticPulp 6y ago
In this case, adverse effects from Bexarotene are virtually guaranteed, even at low doses. This study explored hypothyroidism in even low-dose Bexarotene and found 61 out of 66 patients exhibited hypothyroidism: https://pubmed.ncbi.nlm.nih.gov/30903705/ https://pubmed.ncbi.nlm.nih.gov/30903705/ Bexarotene also significantly elevates cholesterol markers and blood lipids, which would accelerate heart disease and shorten lifespan. The researchers aren’t simply dismissing drugs at the first sign of side effects. We have many drugs on the market with significant contraindications due to adverse side effects in specific populations, and doctors are generally well-informed about testing for these conditions and selecting only suitable drug candidates.
DanBC 6y ago
One of the things not mentioned about bexarotene is that it's very teratogenic. That makes it more difficult (but not impossible) to use it for women. > Materials to support the Pregnancy Prevention Programme in women and girls of childbearing potential taking oral acitretin, alitretinoin, or isotretinoin have been updated. Oral tretinoin and bexarotene do not have a Pregnancy Prevention Programme in light of their oncology indication and specialist care setting. However, healthcare professionals are advised that these medicines are extremely teratogenic and product information should be consulted for contraceptive and pregnancy testing requirements when used in females of childbearing potential. When used for cancer these side effects are very common (greater than 1 in 10) or common (between 1 in 10 and 1 in 100). Some of these are going to be mild and temporary. But some of them are serious. > Alopecia; anaemia; appetite decreased; arthralgia; asthenia; chills; constipation; deafness; diarrhoea; dizziness; dry eye; dry mouth; dyslipidaemia; eye disorders; gastrointestinal discomfort; gastrointestinal disorders; headaches; hyperhidrosis; hypersensitivity; hypoproteinaemia; hypothyroidism; increased risk of infection; insomnia; leucopenia; lymphadenopathy; muscle complaints; nausea; oedema; oral disorders; pain; pseudolymphoma; sensation abnormal; skin nodule; skin reactions; skin ulcer; thyroid disorder; vomiting; weight changes

PragmaticPulp 6y ago

The drug used in this study, Bexarotene, is already approved for cancer treatment and available in the United States and Europe. Using Bexarotene in cancer patients makes sense because the side effects are more tolerable than dying from cancer. Using Bexarotene in Multiple Sclerosis patients doesn’t make sense if the net effect is a worsened quality of life (significant thyroid disease) and a shortened lifespan due to accelerated heart disease (hyperlipidaemia and hypercholesterolaemia).

deleted 6y ago
[deleted]