BYM338 Is A Promising Myostatin Inhibitor But Lacks Clinical Results
While Bimagrumab sounds like a town in far north west NSW of Australia, somewhere west of Goonoo Goonoo, east of Koolyanobbing, and north of Yackandandah, it’s actually a myostatin inhibitor being trialed in both humans and animals for future use in skeletal muscle atrophy and weakness conditions.
It works as an antibody targeting ActRII, which is the receptor that myostatin binds to. Myostatin is what sets the upper limit on muscle growth in humans – for more reading on this see my article on YK11 and Follistatin. Ordinarily, ActRII signals blocks a protein molecule which reduces synthesis. Bimagrumab (BYM338) inhibits ActRII, prevents the blocking of the protein molecule, and protein synthesis continues without check.
The effects on myogenic differentiation were assessed upon treatment with BYM338 using 303 primary human fetal or adult skeletal muscle cells. As shown in Figure 2A by myosin heavy 304 chain (MyHC) staining, BYM338 increased differentiation and fusion 4 days after switching 305 confluent myoblasts to differentiation media, when compared to control culture.
Differentiation is important as it is where a cell becomes more specialized, and for it to have increased 4 days after administering BYM338 shows that it is effective after a short amount of time, backing up the researchers claim that it has a strong binding affinity. In short, it works, and relatively quickly.
The rest of this study deals with in vitro application with cultured cells, which isn’t very interesting nor always applicable. Instead, let’s look at the clinical human trials.
2014: n=14, after 8 weeks patients increased thigh muscle volume by about 7% in both thighs and lbm by 5%, with no serious adverse events and the main adverse events being acne (which ought to be expected) and involuntary muscle contraction. Or the patients were just flexing their new muscles all the time – ‘can’t help it doc, look at these quads tho!’
2016: n=251, four groups, with the first group getting 10mg/kg, second getting 3mg/kg, third getting 1mg/kg, and the fourth acting as control. They received the compound for 2 years (!) by IV administered every 4 weeks. We can disregard this study, so if you just want to skip the next two paragraphs go ahead, otherwise for the purposes of refuting any disinformation around this compound read on.
Between 11%-15% in the groups receiving the compound withdrew, because of physician decision, death (just the one, likely unrelated), and withdrawal by subject or adverse event. The last two made up the vast majority of withdrawals out of all groups. This is compared to placebo which had an 8% withdrawal rate. All three BYM338 groups had a higher lbm ratio than control at the conclusion, but not by a huge amount. The 10mg/kg result was at 102.8, 3mg/kg was at 100.4, 1mg/kg was at 98.3 and control was at 97.2. In all groups, there was a deterioration in quad size including placebo. There was also a very high incidence of Serious Adverse Events, 33.33%, 17.46% and 27.57% against the 3 compound receiving groups respectively, and control had a SAE of 32.26%.
Given all this data, this was clearly a failure – it did not help the patients in this study who all had a debilitating muscle disease called sIBM. None of this data is actually very useful, and imo all this demonstrates is that BYM338 is not a good drug choice for folks with this disease. No other conclusion can really be drawn here. And same with a 2018 study discontinued due to Novartis (research sponsor) terminating it. While there was a huge number of adverse events and deaths, this was in line with the placebo group, and not due to the compound. This is completely unexpected by the way, as the animal trial showed muscle mass increase of 25%-50%. We can forgive Novartis for thinking it applicable in patients with muscular weakness.
Its use for in insulin resistant patients is interesting though, as BYM338 increased lean mass by 2.7% at 10 weeks (reduced fat mass by 7.9%) after a single dose of 30mg/kg given through IV, and improved insulin sensitivity by 20%-40%.
Despite the animal trials, 2014 and the aforementioned study showing the promise for this compound, this drug was approved for clinical trial in patients with a very specific debilitating muscle disease, and frankly it doesn’t seem to be doing much good in that area. I don’t believe that the compound caused a significant increase in adverse events that can’t be explained away. I would however caution everyone before running this compound – we have some very spotty clinical trials, and importantly we don’t have any anecdotal experience like we do with SARMs. You should also be wary about its effects on cardiac hypertrophy, which we have mixed data on. In 2007, it was established that myostatin does not regulate cardiac hypertrophy, but then in 2009 and 2014 two studies came out showing the opposite: myostatin represses hypertrophy of the heart and regulates homeostasis.
So in conclusion, there’s a lot of unknown here and some conflicting data. I suspect that the reduction in myostatin does increase the risk of the LVH at about the same rate as anabolic steroid use. That’s a known risk, one that many take every day. I’m open to that risk, but couple it with the lbm ratio gains demonstrated in the admittedly less than ideal target population will lead me to personally watch this space until I see some anecdotal reports from users.