Last updated August 1, 2022, by Teresa Carvalho, MS
 Fact-checked by José Lopes, PhD
What is Uptravi for PH?
Uptravi (selexipag) is medication given orally or via intravenous infusion (into-the-vein, IV) to delay disease progression and reduce the risk of hospitalization in patients with pulmonary arterial hypertension (PAH).
The therapy, discovered by Nippon Shinyaku, is commercialized by Janssen, part of the Johnson & Johnson family of companies.
How does Uptravi work?
PAH is marked by the narrowing of blood vessels that transport blood through the lungs. The condition is included in Group 1 of the World Health Organization (WHO) classification of pulmonary hypertension.
Uptravi mimics the action of a signaling molecule called prostacyclin, which causes the vessels to relax and dilate, lowering blood pressure.
Who can take Uptravi?
Uptravi is approved for the oral treatment of adults with PAH with WHO functional class (FC) II–III in more than 60 countries. Notably, WHO-FC is a tool used to measure disease severity in patients with PAH. Patients are allocated into class I, II, III, or IV; a higher class means more severe disease (greater functional impairment).
The U.S. Food and Drug Administration approved Uptravi in 2015. The following year, the treatment was approved in Europe and Canada.
In 2021, Uptravi received FDA approval for intravenous treatment in patients who are temporarily unable to take oral therapy, such as those who need hospitalization.
Who should not use Uptravi?
Uptravi should not be used by people who have allergic reactions to the active substance (selexipag) or to any of the therapy’s components.
The therapy should not be administered in people who are being treated with strong CYP2C8 inhibitors, such as gemfibrozil, because this medication may affect how Uptravi works and also lead to side effects.
How is Uptravi administered?
For patients treated with oral tablets, the recommended starting dosage is 200 micrograms (mcg) taken twice daily. The dose can be increased at weekly intervals to the highest tolerated dose up to 1600 mcg twice daily. It’s available at the following strengths:
- 200 mcg, contained in light yellow tablets debossed with 2
- 400 mcg in red tablets debossed with 4
- 600 mcg in light violet tablets debossed with 6
- 800 mcg in green tablets debossed with 8
- 1000 mcg in orange tablets debossed with 10
- 1200 mcg in dark violet tablets debossed with 12
- 1400 mcg in dark yellow tablets debossed with 14
- 1600 mcg in brown tablets debossed with 16
Patients are recommended to take the medication with food to improve tolerability. Tablets should be swallowed whole and not be split, crushed, or chewed.
For those treated with Uptravi IV, the treatment is available as a powder that should be reconstituted and diluted. The recommended dose is determined by the dose the patient is taking in oral tablets, as follows:
- 225 mcg, corresponding to 200 mcg tablets
- 450 mcg, corresponding to 400 mcg tablets
- 675 mcg, corresponding to 600 mcg tablets
- 900 mcg, corresponding to 800 mcg tablets
- 1125 mcg, corresponding to 1000 mcg tablets
- 1350 mcg, corresponding to 1200 mcg tablets
- 1575 mcg, corresponding to 1400 mcg tablets
- 1800 mcg, corresponding to 1600 mcg tablets
The IV form should be given as an 80-minute infusion, twice daily.
Uptravi in clinical trials
Phase 2 trials
The safety and effectiveness of Uptravi were first examined in a Phase 2 proof-of-concept study (NCT00993408) in 43 patients with PAH. Results of the study showed a statistically significant reduction (by 30.3%) in pulmonary vascular resistance — the resistance to blood flow through pulmonary circulation — after 17 weeks of Uptravi treatment compared with a placebo. Uptravi was also well tolerated.
GRIPHON and TRITON trials
A Phase 3 clinical trial called GRIPHON (NCT01106014) assessed Uptravi’s safety and its effects on the risk of death or complication in 1,156 patients with PAH. Enrolled patients could not be receiving any treatment for PAH other than a stable dose of an endothelin receptor antagonist (ERA), a phosphodiesterase type 5 inhibitor (PDE-5i), or both.
In 2015, a study reported that the risk of death or a complication was significantly lower in patients treated with Uptravi than with placebo. Further results showed Uptravi slowed the progression of connective tissue disease associated with PAH.
In 2018, another analysis of this study concluded that the addition of Uptravi to ERA and PDE-5i provides a benefit for patients with PAH.
TRITON was a Phase 3 trial (NCT02558231) designed to compare the effectiveness and safety of an initial triple oral treatment of three blood pressure medications — Opsumit (macitentan), Adcirca (tadalafil), and Uptravi — in newly diagnosed, previously untreated PAH patients. The study found the Uptravi combination significantly reduced the risk of first disease progression by 41% compared to the standard initial therapy, and also showed a trend toward better survival rates. However, the triple therapy was no better than the Opsumit and Adcirca combo only at lowering pulmonary vascular resistance and in assessments of cardiovascular health and disease severity.
An analysis of these Phase 3 trials found that Uptravi significantly reduced the risk of disease progression by 52%, compared to a placebo.
TRANSIT-1 trial
The safety and tolerability of the transition from inhaled Tyvaso (inhaled treprostinil) to oral Uptravi were assessed in a Phase 3b clinical trial called TRANSIT-1 (NCT02471183). A total of 34 PAH patients were enrolled and the transition period took 16 weeks. Results showed that switching is safe and considered convenient by the patients.
Other Phase 3 trials
Another Phase 3 trial (NCT03187678)Â assessed switching from oral to IV Uptravi in patients with stable PAH. In addition to safety, the study aimed at verifying the tolerability and pharmacokinetics (the movement into, through and out of the body) of the IV therapy. The trial found that IV Uptravi is safe and well tolerated by patients who reported mild side effects from the transition, with the most frequent being common to oral treatment.
A Phase 3 trial (JapicCTI: 163279) enrolled 78 Japanese patients with inoperable or persistent chronic thromboembolic pulmonary hypertension (CTEPH), a form of pulmonary hypertension caused by blood clots in the lungs. The study found that Uptravi significantly improved blood flow parameters in those patients, although it did not significantly alter measures of physical abilities.
TRACE trial
The TRACE trial, a Phase 4 study (NCT03078907), was intended to determine the effect of Uptravi compared with a placebo on the daily physical activity of PAH patients. During the trial, patients used a wearable wrist device called an actigraph to monitor their physical activity in a real-life environment. In addition, the researchers assessed PAH symptoms and their impact on the patients’ daily lives. The study found no statistically significant differences in daily life physical activity between the two groups of patients. According to the scientists, patients in this study were not actively encouraged to increase activity, which may have limited identifying short-term improvements.
SPHERE trial
SPHERE (NCT03278002), a U.S.-based study using a real-world registry collected data from a wide range of adults being treated with Uptravi. Data from the first 500 patients reported that 76% either had no increase or experienced a decline in their risk of death over one year. According to the researchers, these results highlight the importance of risk assessments in determining treatment goals in people with PAH.
Common side effects of Uptravi
The most common side effects of Uptravi include:
- headache
- skin flushing
- nausea
- vomiting
- low red blood cell count
- diarrhea
- pain in muscles, jaw and extremities
Liquid accumulation in the lungs
Patients with pulmonary veno-occlusive disease, a rare form of pulmonary hypertension, are at high risk of accumulating fluids in the lungs, an issue called pulmonary edema. If symptoms occur, the treatment should be discontinued.
Use with other medications
Use of moderate CYP2C8 inhibitors (including clopidogrel, deferasirox and teriflunomide) while on treatment with Uptravi increases the exposure to selexipag. Uptravi dosage should be reduced to once daily. Using Uptravi together with CYP2C8 inducers, such as rifampin, reduces the exposure to selexipag. In this case, Uptravi dosage should increase up to twice the dose.
Use in people with liver damage
For patients with moderate liver injury, the starting dose of oral treatment is 200 mcg once daily. Increments of 200 mcg once daily at weekly intervals may be considered, as tolerated. People with severe liver damage are recommended to avoid Uptravi.
Use in pregnancy and breastfeeding
According to animal data, selexipag did not cause harm to the developing fetus. However, there’s a lack of studies of Uptravi in pregnant women. Women who are pregnant or plan to become pregnant should talk with their healthcare team about these issues. It is also unknown if selexipag can pass to breast milk. As such, women are recommended to either discontinue Uptravi or breastfeeding.
Pulmonary Hypertension News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
