Anamorelin increases lean mass but not grip strength in cachexia

How does anamorelin work?

Anamorelin is an orally active, selective agonist at the growth hormone secretagogue receptor, the same receptor ghrelin activates. Stimulating that receptor triggers pulsatile growth hormone release from the pituitary, which drives hepatic IGF-1 production, and it independently activates hypothalamic circuits that increase appetite and food intake.

In the Phase 3 program, that mechanism produced a large IGF-1 rise. Pooled trial data put the weighted mean difference at roughly 51 ng/mL over placebo ^[2]. The appetite record for ghrelin agonists covers that side of the mechanism.

What did ROMANA 1 and ROMANA 2 find?

ROMANA 1 and ROMANA 2 found that anamorelin increased lean body mass over placebo across 12 weeks and left handgrip strength unchanged ^[4].

The two pivotal randomized, double-blind, placebo-controlled Phase 3 trials enrolled 484 and 495 patients respectively, all with inoperable stage III or IV non-small-cell lung cancer and cachexia, defined as at least 5% weight loss in six months or a BMI under 20 ^[4]. The dose was anamorelin 100 mg once daily.

Handgrip strength was the second co-primary endpoint, and it did not improve over placebo in either trial ^[4]. That is randomized, adequately powered, Phase 3 evidence, the highest grade available for anamorelin, and the strength result is a direct, prespecified failure rather than an underpowered secondary miss.

Did the Japanese trials show the same pattern?

Yes. The Japanese regulatory package reproduced the split twice. The Phase 2 trial in Japanese NSCLC patients found lean body mass gains of 0.55 kg on placebo versus 1.15 kg on anamorelin 100 mg, with no detected effect on handgrip strength ^[5].

The subsequent Japanese Phase 3 trial, ONO-7643-04, found an even larger lean body mass separation, 1.38 kg versus −0.17 kg (P<.0001). It reported no group difference in handgrip strength or in six-minute walk distance, a second functional measure that also failed to move ^[6].

Three independent randomized trials, run years apart on two continents, produced the identical pattern: robust mass gain, absent functional gain.

Why did anamorelin add mass without adding strength?

Lean body mass by DXA captures fat-free tissue broadly, and growth hormone and IGF-1 elevation can expand several of those compartments without building contractile muscle.

DXA lean mass includes skeletal muscle, organ mass, connective tissue, and total body water. GH and IGF-1 elevation can expand several of these without producing a proportional increase in myofibrillar protein or improving the neuromuscular signaling that generates grip force. Appetite stimulation on its own, by raising caloric and protein intake, can also add tissue mass through pathways unrelated to contractile quality.

None of the anamorelin trials measured muscle biopsy composition or fiber type, so that account is the leading explanation for the divergence rather than a demonstrated finding. The assumption it corrects is the one embedded in most consumer-facing writing about ghrelin secretagogues, including MK-677 and the GHRP peptides: that raising GH and IGF-1 straightforwardly builds functional muscle. That assumption also shapes writing about MK-677.

Do meta-analyses change the anamorelin strength conclusion?

Pooling more patients does not rescue the strength endpoint in the earlier analyses. A 2017 systematic review and meta-analysis of four randomized trials found a significant lean body mass benefit (P<0.00001, no heterogeneity) and a significant body weight benefit, and reported no significant difference in non-dominant handgrip strength across the three trials that measured it ^[1].

A 2023 meta-analysis of five trials and 1,331 participants found significant increases in body weight, lean body mass, fat mass, IGF-1, and IGFBP-3, reinforcing that anamorelin reliably moves body composition and its hormonal drivers ^[2].

A more recent umbrella review of systematic reviews across cachexia pharmacotherapies reports that anamorelin improved lean body mass, grip strength, body weight, IGF-1, and IGFBP-3, and ranks it the most promising agent among those studied. The same review grades that evidence, including the grip strength component, as low to very low certainty ^[3]. That grading is consistent with the primary trial data showing no effect and with the earlier meta-analyses showing no significant pooled effect, rather than a contradiction of them.

A positive grip signal appears only in broader syntheses with low certainty grades or in inflammation-stratified subgroups ^[3]⁠^[7], never in the primary, prespecified Phase 3 comparison ^[4].

Did any patients gain strength on anamorelin?

One post hoc subgroup did. In pooled ROMANA patients with the highest baseline systemic inflammation, a modified Glasgow Prognostic Score of 2, anamorelin improved handgrip strength and an anorexia/cachexia quality-of-life subscale alongside the weight and body composition gains ^[7].

That analysis is exploratory, non-prespecified subgroup evidence. It is useful for generating a hypothesis about who might benefit functionally, and it does not override the primary, prespecified result across the full trial populations.

What dose of anamorelin was studied, and how large were the effects?

The dose across the Phase 2 and Phase 3 program was 100 mg orally once daily, with a 50 mg arm also tested in the earlier Japanese Phase 2 trial ^[5].

Effect sizes cluster in a consistent range. Lean body mass gains ran roughly 1.1 to 1.4 kg over 12 weeks versus placebo, and body weight gains came to a pooled weighted mean difference of about 1.56 kg ^[2]⁠^[6]. Fat mass also increased, with a pooled weighted mean difference near 1.0 kg ^[2], so part of the body composition change is not lean tissue at all.

Why did the FDA and EMA reject anamorelin?

The missing handgrip endpoint from ROMANA 1 and ROMANA 2 is the specific efficacy gap most consistently cited for the rejections. Both trials were designed with function as a co-equal endpoint to mass, not a secondary afterthought ^[4].

The European Medicines Agency's Committee for Medicinal Products for Human Use issued a negative opinion in 2017, and the FDA did not approve anamorelin. Japan's regulatory authority approved it as Adlumiz for cancer cachexia in 2021, following its own Phase 2 and Phase 3 program ^[5]⁠^[6]. A drug that grows tissue without improving what the tissue does is a recurring pattern, as a muscle drug that raised volume without strength also shows.

What is still unknown about anamorelin?

Four questions remain open after the Phase 3 program:

• Tissue composition. No cited trial measured muscle biopsy histology, fiber-type composition, or contractile protein content, so the explanation for the mass-strength split remains inference.
• Longer treatment. Whether treatment beyond 12 weeks would eventually produce a strength signal is untested.
• The inflammation subgroup. Whether the improved grip strength in high-inflammation patients ^[7] reflects a reproducible biological interaction or a post hoc artifact of multiple subgroup testing has not been confirmed in a prospective trial.
• Other ghrelin agonists. Whether non-oral GHRPs or MK-677 show the same mass-strength split is not addressed by any of the anamorelin studies cited. Anamorelin is the only member of the class with trial evidence at this level to check against.