Tecfidera efficacy & potential toxicity

[NHE]

I just finished reading the prescribing information for Tecfidera. Of the two studies cited, one did not show a significant effect on disease progression.

Tecfidera had a statistically significant effect on all of the relapse and MRI endpoints described above. There was no statistically significant effect on disability progression. The Tecfidera 240 mg three times daily dose resulted in no additional benefit over the Tecfidera 240 mg twice daily dose.

· · · · · · · · · · · · · · · · · · · Tecfidera · Placebo · P ·
Proportion with disability progression · 13% · · · · 17% · 0.25

I also found that this section seemed to stand out...

Carcinogenicity studies of dimethyl fumarate (DMF) were conducted in mice and rats. In mice, oral administration of DMF (25, 75, 200, and 400 mg/kg/day) for up to two years resulted in an increase in nonglandular stomach (forestomach) and kidney tumors: squamous cell carcinomas and papillomas of the forestomach in males and females at 200 and 400 mg/kg/day; leiomyosarcomas of the forestomach at 400 mg/kg/day in males and females; renal tubular adenomas and carcinomas at 200 and 400 mg/kg/day in males; and renal tubule adenomas at 400 mg/kg/day in females. Plasma MMF exposure (AUC) at the highest dose not associated with tumors in mice (75 mg/kg/day) was similar to that in humans at the recommended human dose (RHD) of 480 mg/day.

In rats, oral administration of DMF (25, 50, 100, and 150 mg/kg/day) for up to two years resulted in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150 mg/kg/day. Plasma MMF AUC at the lowest dose tested was lower than that in humans at the RHD.

So, rats given effective doses lower than the prescribed dose for people developed stomach cancers yet there's no comment if any carcinogenic effects were seen in people

In addition...

Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of DMF, and in a chronic oral toxicity study evaluating a combination of four fumaric acid esters (including DMF) in rats.

[whyRwehere]

Yes, hate to not be enthusiastic, but we all know how their last 2 blockbuster MS drugs ended up being less than expected, and as one finds out more about this drug, it seems Biogen's biggest success is its marketing. Thanks, but no thanks.

[neutron032]

NHE,

I don't think you understand what the study says. At "doses of 25, 75, 200, and 400 mg/kg/day" caused cancer in mice and rats. In my case, I weigh 87 kg, in order to take a comparable dose I would have to take a dose of 2175, 6525, 17400, and 34800 mg/day.

This is significantly below the recommended dose of 240 mg twice a day.

[NHE]

I don't think you understand what the study says. At "doses of 25, 75, 200, and 400 mg/kg/day" caused cancer in mice and rats. In my case, I weigh 87 kg, in order to take a comparable dose I would have to take a dose of 2175, 6525, 17400, and 34800 mg/day.

I agree with you. If it was as simple as a mathematical extrapolation of the dose, then it would not have been worth mentioning. However, the prescribing information seems a little thin, especially compared to some other medications that I've looked into which were 32 pages long, so I think it's important to carefully examine every sentence.

In rats, oral administration of DMF (25, 50, 100, and 150 mg/kg/day) for up to two years resulted in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150 mg/kg/day. Plasma MMF AUC at the lowest dose tested was lower than that in humans at the RHD.

So, it appears to be saying that at effective doses lower than that given to humans, as measured by the plasma monomethyl fumarate area under the curve concentrations, rats developed cancers.

NHE

[neutron032]

I read the study and I took that to mean; in order to get a comparable plasma concentration of the metabolite monomethyl fumarate, MMF, rats had to be dosed, with dimethyl fumarate, at least 25 mg/kg/day. That is five times the dose of dimythel fumarate a 190 lb man would get taking tecfidera as prescribed.

You are making a big leap assuming that it is the plasma concentration of MMF is the cause of the testicular cancers. The only thing that this sentence, "Plasma MMF AUC at the lowest dose tested was lower than that in humans at the RHD.", shows to me is that humans are five times more efficient in metablolizing dimethyl fumarate into monoethyl fumarate.

The only thing that you posted that would give me cause for concern is the last block in your first message:

"Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of DMF, and in a chronic oral toxicity study evaluating a combination of four fumaric acid esters (including DMF) in rats."

I would be concerned because it showed toxicity at clinically relevant doses. Cancers at five times the clinical dose would not give me pause, if I was thinking about switching to tecfidera. I am not considering it because my current medication, rebif, seems to be working.

[NHE]

The only thing that you posted that would give me cause for concern is the last block in your first message:

"Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of DMF, and in a chronic oral toxicity study evaluating a combination of four fumaric acid esters (including DMF) in rats."

I would be concerned because it showed toxicity at clinically relevant doses. Cancers at five times the clinical dose would not give me pause, if I was thinking about switching to tecfidera. I am not considering it because my current medication, rebif, seems to be working.

Do we know how Biogen determined what a "clinically relevant" dose actually is? Was it by comparing MMF AUC's? I could see a high DMF dose being related to the stomach cancers, but I don't see how it could affect testicular cancer unless the DMF was being absorbed into the bloodstream without being converted to MMF. Do we know if the test animals absorbed DMF directly? It seems that in humans that DMF has a particularly short half-life and MMF is thought to be the principle active agent.

NHE

[civickiller]

i may have little understanding of clinical trails but it doesnt make sense to test in unrealistic doses

rats given a lower dose still developed stomach cancer, so would it be fair to say that in any dose it can be cancerous?

[hlsuderlund]

I'm feeling like one of those poor OD'd rats right now, so I have very little doubt that for some people, you don't need 5 times the therapeutic dose. No need to clarify dosage, as this will be the same as all other meds, some can take it and some can't. I and my family are greatly disheartened after the tremendous build up to the release of this medication. I just hope those who can take it don't suffer a worse fate 2 decades down the line, and I pray for all of us.