PT-141 side effects and results in clinical trials
In the phase 3 trials, the most common side effects of PT-141 (bremelanotide) were nausea (40.0% vs 1.3% on placebo), flushing (20.3%) and headache (11.3%), and most were mild to moderate. The measured results were small but statistically significant gains in sexual desire and falls in related distress in premenopausal women, and stronger erectile responses in men.
The side effects of bremelanotide are well documented because it went through a full clinical programme: 3,500 subjects in 43 studies. In the integrated double-blind phase 3 data (n=1,247), nausea affected 40.0% on bremelanotide versus 1.3% on placebo, flushing 20.3% versus 1.3%, headache 11.3% versus 1.9% and injection site reactions 5.4% versus 0.5%. Nausea was the most common reason for stopping. There were no deaths, and a few subjects had serious adverse events.
Blood pressure is the second safety theme. In a 397-woman ambulatory monitoring trial, systolic pressure rose by about 2.4–3.2 mmHg over placebo in the 4 hours after the 1.25 and 1.75 mg doses. Peaks usually lasted under 15 minutes, and heart rate fell by 4.6–4.7 bpm at 1.75 mg. Focal hyperpigmentation was rare at labelled dosing, but it occurred in more than one-third of subjects after up to 16 consecutive daily doses.
On results, the RECONNECT trials found statistically significant increases in desire (integrated 0.35 on the FSFI desire domain) and falls in distress (−0.33) compared with placebo. Subgroup analyses found the effect across age, weight, BMI and testosterone levels, with few exceptions. In men, subcutaneous doses above 1.0 mg produced measurable erections, and a 10 mg intranasal dose gave positive results in 33.5% versus 8.5% of sildenafil non-responders.
These results are contested. A 2024 re-analysis found effect sizes from nil to small on eight previously unpublished RECONNECT outcomes. It concluded that the benefits are statistically modest and rest on measures with little validity evidence in HSDD. A 2020 systematic review also described the clinical benefit as possibly modest.
Adverse events reported
| Event | As reported | Source |
|---|---|---|
| Nausea | 40.0% vs 1.3% placebo (integrated phase 3, n=1,247); most common reason for discontinuation | Clayton AH et al. |
| Flushing | 20.3% vs 1.3% placebo | Clayton AH et al. |
| Headache | 11.3% vs 1.9% placebo | Clayton AH et al. |
| Injection site reactions | 5.4% vs 0.5% placebo | Clayton AH et al. |
| Focal hyperpigmentation | Rare at labelled dosing; more than one-third of subjects after up to 16 consecutive daily doses | Clayton AH et al. |
| Blood pressure rise | Systolic up about 2.4–3.2 mmHg vs placebo at 1.25–1.75 mg, 0–4 h after dosing; peaks usually under 15 min | White WB et al. |
| Heart rate fall | −4.6 to −4.7 bpm at 1.75 mg in the 0–4 h interval | White WB et al. |
| Drug-related adverse effects (intranasal, men) | More frequent with 10 mg intranasal bremelanotide than placebo (p=0.01); types not listed in the abstract | Safarinejad MR et al. |
| Drug interactions | Lowered plasma indomethacin and naltrexone; most other interactions not clinically significant | Clayton AH et al. |
Outcomes measured
| Outcome | Result as reported | Source |
|---|---|---|
| Sexual desire (FSFI desire domain), women with HSDD | Integrated increase 0.35 vs placebo (P<.001) over 24 weeks | Kingsberg SA et al. |
| Distress about low desire (FSDS-DAO item 13) | Integrated change −0.33 vs placebo (P<.001) | Kingsberg SA et al. |
| Satisfying sexual events per month | +0.7 vs +0.2 placebo, pooled 1.25/1.75 mg (p=0.0180), 12 weeks | Clayton AH et al. |
| Responder rates, 1.75 mg (phase 2b) | Significant vs placebo on all 7 endpoints (P ≤ .03) | PMID 31277966 |
| Erectile response, healthy men (RigiScan) | Significant at subcutaneous doses above 1.0 mg | Rosen RC et al. |
| Erectile response, sildenafil non-responders (intranasal 10 mg) | Positive results in 33.5% vs 8.5% placebo (p=0.03) | Safarinejad MR et al. |
| Erectile response with sildenafil (intranasal 7.5 mg) | Greater than sildenafil alone | Diamond LE et al. |
| Desire, women with arousal disorder (intranasal 20 mg) | More reported moderate or high desire vs placebo (P=0.0114); no significant change in vaginal vasocongestion | Diamond LE et al. |
| Validity of RECONNECT outcomes (re-analysis) | Effect sizes nil to small on 8 previously unpublished outcomes | PMID 36809187 |
What the studies don't show
Almost all of the modern data are in premenopausal women with HSDD using the 1.75 mg subcutaneous product. The data in men and on the nasal route come from smaller trials run before 2010. The size of the benefit is disputed in the literature, and the trials were not designed to show safety over many years.