The year in pulmonary arterial hypertension (PAH) brought hope for new treatments on the horizon and ready to cross the finish line.
Novel Sotatercept
PAH patients with treated with the investigational drug sotatercept showed significant improvements in pulmonary vascular resistance (PVR) and 6-minute walk distance in phase II findings from the PULSAR study presented at the virtual American Thoracic Society (ATS) meeting.
At week 24, the 0.7 mg/kg dose cut PVR by a relative 33.9%, compared with a 2.1% reduction in patients in the placebo group (P<0.0001).
Sotatercept is the first in a new class of fusion proteins designed as a selective ligand trap for the TGF-beta superfamily to rebalance pro- and anti-signaling pathways for the serine receptor kinase bone morphogenetic protein receptor type II (BMPR-II), a key molecular driver of PAH.
Initial data from 10 PAH patients in the ongoing phase II SPECTRA trial of sotatercept reported at the virtual American Heart Association meeting showed PVR decreased from 576 dyn-sec/cm5 at baseline to 369 dyn-sec/cm5 at 24 weeks.
Acceleron announced it would start the phase III STELLAR trial of sotatercept in PAH by the end of 2020 with two other trials of early and later-stage intervention coming in 20210.
Inhaled Treprostinil
Another development of note was release of results from the phase III INSPIRE trial, testing a novel inhaled dry powder formulation of treprostinil for PAH.
Exploratory analyses from that trial presented at the virtual ATS meeting showed significant quality of life benefits to the inhaled prostacyclin vasodilator along with better 6-minute walk distance (6MWD).
Inhaled treprostinil also improved exercise capacity in patients with pulmonary hypertension and interstitial lung disease in the phase III INCREASE trial. The drug increased 6MWD by 21 meters more than seen with placebo after 16 weeks (P=0.0043) in findings reported at the virtual ATS meeting.
Martin Kolb, PhD, of McMaster University in Ontario, told MedPage Today that the findings offer more evidence that targeting the blood vessels can be an effective strategy for addressing fibrosis. “The lung is made up of both air tubes and blood vessels, and much of the research has been focused on either one or the other. But there is close interaction between the two.”
Developer Liquidia Technologies applied to the FDA for marketing approval, but on Nov. 25, the agency turned it down, citing manufacturing and “device biocompatibility” issues. Liquidia said additional trials should not be necessary to win final approval.
Other Research
For the first drug regimen in newly-diagnosed PAH, triple oral therapy with selexipag (Uptravi), macitentan (Opsumit) and tadalafil wasn’t better than double drug therapy with macitentan and tadalafil for hemodynamics, NT-proBNP, or functional capacity at 26 weeks in the TRITON trial.
In a proof-of-concept study, PAH patients had a unique gut microbiome profile — heavy on Coriobacteriales bacteria associated with trimethylamine (TMA)/trimethylamine N-oxide (TMAO) and purine production.
Altogether, the presence and absence of 30 individual bacterial species pinpointed presence of PAH with 83% accuracy.
Some potential biomarkers of PAH “could be derived from altered bacterial functions in patients with PAH,” the researchers concluded. “Therefore, identification and characterization of PAH specific bacteria and metabolites in both gut and lung hold promise for the development of innovative strategies for the control and treatment of PAH by modification of diet, prebiotics, microbiota transplantation, and pro/antibiotics.”
In a separate study, women who took sildenafil (Viagra) during pregnancy to treat fetal growth restriction did not see reduced risk of morbidity and mortality in their babies but was linked to 3.67-fold elevated risk of neonatal pulmonary hypertension as a complication in a randomized clinical trial from the Netherlands.
A systematic review of pulmonary hypertension rehabilitation studies suggested expanding outcome measures beyond just body function and structure to also reflect physical activity and participation in society.
Kickback Crackdown
The Justice Department’s crackdown on alleged kickbacks continued to impact PAH drugmakers this year. Gilead Sciences agreed to pay $97 million to resolve claims that it violated the False Claims Act by allegedly using a charitable foundation to pay the copays of Medicare patients taking ambrisentan (Letairis).
“Like its competitors, Actelion and United Therapeutics, Gilead used data from CVC [Caring Voice Coalition] that it knew it should not have, and effectively set up a proprietary fund within CVC to cover the co-pays of just its own drug,” according to a Justice Department press release. “Such conduct not only violates the anti-kickback statute, it also undermines the Medicare program’s co-pay structure, which Congress created as a safeguard against inflated drug prices. During the period covered by today’s settlement, Gilead raised the price of Letairis by over seven times the rate of overall inflation in the United States.” Gilead, however, did not admit guilt in the settlement agreement.
United Therapeutics had settled similar allegations in 2017 for $210 million related to its PAH drugs, including tadalafil (Adcirca) and treprostinil (Remodulin, Tyvaso, and Orenitram).
And facing such charges as well, related to its bosentan (Tracleer), iloprost (Ventavis), epoprostenol (Veletri), and macitentan (Opsumit) products, Actelion reached a settlement for $360 million in 2018.
Source: MedicalNewsToday.com
