C tier · mixed
It carries the largest genuine randomised human dataset in this index — a 203-patient phase 2 published in The Lancet plus a completed phase 3 — but it is approved nowhere, was not approved by COFEPRIS in November 2024, and has consistent cardiovascular and psychiatric signals.
tesofensine
Tesofensine is a triple monoamine (noradrenaline, serotonin, dopamine) reuptake inhibitor that produced substantially greater weight loss than placebo in a published 24-week randomised phase 2 trial in obesity. It has real human evidence behind it, but it is not an approved medicine in any market identified for this index, and dose-dependent increases in blood pressure, heart rate and sleep or mood disturbance recur across trials.
the explanation
Tesofensine raises three brain chemicals that reduce appetite, and in a proper randomised trial people on it lost a lot more weight than people on placebo. It has also repeatedly raised blood pressure and heart rate and caused insomnia and anxiety, and no regulator has approved it.
regulatory status
Not approved in the US or EU; Mexican application not approved as of the last verified filing
Development for obesity is by Saniona with partner Medix. COFEPRIS' technical committee gave a favourable opinion in February 2023, but on 6 November 2024 Saniona disclosed that the Mexican application had not been approved, with Medix stating the decision appeared not to have been based on the full submitted data package. In February 2025 Medix said it had identified a path forward and would resubmit a revised dossier. No confirmed marketing approval in any jurisdiction was verifiable for this index.
how it works · proposed mechanism
Tesofensine blocks the reuptake of all three major monoamines at once, sustaining signalling that suppresses appetite.
Noradrenaline transporter blockade
NET inhibition is the most potent of the three, with a reported IC50 of 1.7 nM. This is the arm most closely tied to both the appetite effect and the observed rises in blood pressure and heart rate.
Serotonin and dopamine reuptake
SERT (IC50 11 nM) and DAT (IC50 65 nM) inhibition add to the anorectic effect, with the relatively weak dopamine activity cited as the reason it failed in Parkinson's disease. The comparatively modest DAT engagement is also the basis for arguments about low abuse potential.
Very long exposure kinetics
Parent half-life is around 220 hours with an active metabolite around 374 hours, so exposure accumulates for weeks before steady state. Any interaction or adverse effect therefore persists long after the last dose.
what’s reported
evidence shape
6 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
The efficacy is real and was published in The Lancet, which is more than almost anything else in this index can say — but the same trials show blood pressure rising at the top dose, heart rate rising at therapeutic doses, and adverse-event withdrawals at roughly twice the placebo rate. The developer's response was to co-formulate it with a beta-blocker, which is a clear statement about how seriously the sponsor took the cardiovascular signal.
key published findings
- Human trial: TIPO-1, a randomised double-blind placebo-controlled 24-week phase 2 in 203 obese patients across five Danish centres, reported mean weight loss of 2.2 kg on placebo versus 6.7 kg (0.25 mg), 11.3 kg (0.5 mg) and 12.8 kg (1.0 mg); 161 of 203 completed (Astrup et al., Lancet 2008;372:1906-1913).
- Human trial: placebo-subtracted mean weight loss in TIPO-1 was 4.5%, 9.2% and 10.6% at 0.25, 0.5 and 1.0 mg respectively — approximately double what was being achieved by the obesity drugs available at the time.
- Human safety: blood pressure was increased in the 1.0 mg group, heart rate increases of up to about 8 bpm have been reported at 0.25-0.5 mg, and withdrawal for adverse events was 13% on tesofensine versus 6% on placebo; common events were dry mouth, headache, nausea, insomnia, diarrhoea and constipation.
- Human trial: Tesomet (tesofensine plus metoprolol) in hypothalamic obesity, a 24-week randomised placebo-controlled phase 2 in 21 adults, produced −6.3% placebo-subtracted weight loss (P=0.017) with no significant between-group difference in heart rate or blood pressure — but sleep disturbance in 50% versus 13% on placebo, one serious adverse event of exacerbated anxiety leading to discontinuation, and one case of paranoia (Huynh et al., Eur J Endocrinol 2022;186:687-700).
- In vitro: transporter inhibition reported at NET 1.7 nM, SERT 11 nM and DAT 65 nM; the weak dopamine activity is cited as explaining both the Parkinson's disease failures and a low abuse-potential argument.
limitations of the evidence
- The pivotal phase 3 results have been described in sponsor communications as confirming phase 2 efficacy, but a full peer-reviewed publication of that trial was not verifiable for this index — the strongest published human evidence remains the 2008 phase 2.
- The Tesomet hypothalamic-obesity trial randomised only 21 patients with 18 completers, which is too small to characterise safety and studies a combination product rather than tesofensine alone.
- No long-term cardiovascular outcome trial has been published, which matters because the class of centrally acting monoaminergic anorectics has a history of post-approval cardiovascular problems, and the very long half-life means exposure cannot be quickly withdrawn.
documented safety signals
- Dose-dependent blood pressure increase, documented in the 1.0 mg arm of the Lancet phase 2, with reported increases of roughly 1-3 mmHg at lower doses.
- Heart rate increase of up to about 8 bpm at therapeutic doses — significant enough that the sponsor developed a fixed combination with the beta-blocker metoprolol specifically to blunt it.
- Psychiatric and sleep signals: insomnia was dose-dependent in the phase 2; in the Tesomet trial sleep disturbance occurred in 50% versus 13% on placebo, one participant discontinued for exacerbated pre-existing anxiety recorded as a serious adverse event, and one case of paranoia was reported.
- Adverse-event withdrawal rate of 13% versus 6% on placebo in the phase 2.
- The terminal half-life of roughly 9 days (16 days for the active metabolite) means any adverse effect or drug interaction persists for weeks after discontinuation.
- As a serotonin reuptake inhibitor it carries the theoretical serotonergic-interaction risk common to that class, compounded by the exceptionally long washout.
identity
| full name | Tesofensine (NS2330) |
| category | Metabolic |
| modality | small molecule |
| formula | C17H23Cl2NO |
| molar mass | 328.28 g/mol |
| cas | 195875-84-4 |
| half-life | Approximately 220 hours (about 9 days) for the parent compound; the major CYP3A4 metabolite M1 (NS2360) is reported at roughly 374 hours (about 16 days) |
laboratory handling
| storage | Reference-standard material is stored at 4 °C protected from light; solutions at -80 °C for approximately 6 months or -20 °C for approximately 1 month, protected from light (MedChemExpress product data). |
| solubility | Poorly water-soluble. Reported at 2 mg/mL (6.09 mM) in DMSO with sonication and warming; in vivo preparations reported using 0.9% saline. |
| co-studied with | The only combination with published randomised human data is Tesomet, a fixed combination with the beta-blocker metoprolol developed explicitly to counter the heart-rate increase; in that 21-patient trial heart rate and blood pressure did not differ significantly from placebo. Combination with other serotonergic agents or monoamine oxidase inhibitors is a recognised theoretical interaction concern for this drug class, and the multi-week washout means separation in time is not straightforward. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
6 citedSaniona AB · 2026 · official
Saniona AB / Nasdaq company announcement · 2024 · official
Saniona AB company announcement · 2025 · official
The Lancet 2008;372:1906-1913 · 2008 · randomized
European Journal of Endocrinology 2022;186(6):687-700 · 2022 · randomized
Wikipedia · 2026 · reviews
others in Metabolic