Disease Analysis: Pulmonary Hypertension

Disease Overview

Pulmonary arterial hypertension is one of a group of rare and life-threatening diseases collectively known as pulmonary hypertension (PH). Each PH subgroup shares similar pathophysiology, clinical presentation, and therapeutic approaches. The diseases are characterized by abnormal vascular proliferation and remodeling of the small pulmonary arteries and arterioles, vasoconstriction, and in situ thrombosis. This leads to increased pulmonary arterial pressure and localized hypertension, which can eventually result in heart failure.

Report Highlights

• Datamonitor Healthcare estimates that in 2018, there were approximately 218,500 prevalent cases of pulmonary arterial hypertension (PAH) in individuals of all ages worldwide, and forecasts that number to increase to 241,800 prevalent cases by 2027.
• Datamonitor Healthcare expects the pulmonary hypertension (PH) market to expand over the forecast period due to the approvals of novel therapies, label expansions into non-PAH subtypes, and FDA clearance of specialist devices. Moreover, the increased number of trials demonstrating improved morbidity/mortality data for marketed brands and a shift to early implementation of triple combination therapy will also drive revenue growth in the PH market.
• Current treatments are solely symptomatic and function by targeting three pathways controlling vasodilation, namely the endothelin, nitric oxide, and prostacyclin pathways. For WHO FC II and III treatment-naïve patients, dual combination therapy with endothelin receptor agonists (ERAs) and phosphodiesterase 5 inhibitors (PDE5is) is the first-line treatment strategy, while monotherapy with a prostacyclin is a first-line therapy for WHO FC IV patients, with ERAs and PDE5is positioned as add-ons. Actelion’s TRITON study, which investigated the use of a triple combination of Opsumit (ERA), Adcirca (PDE5i), and Uptravi (prostacyclin) in WHO FC II and III patients, failed to achieve the primary endpoint of an improvement in pulmonary vascular resistance. Notably, there was a numerical improvement of 41% in hospitalization and all-cause death; however, this was not statistically significant. In support of this positive trend, a post-hoc pooled analysis of patients from the GRIPHON and TRITON trials reached statistical significance, with the rate of disease progression being reduced by 52%. If additional larger trials reveal a significant clinical benefit in disease progression, this will allow prostacyclins to build upon the prevailing trend towards early implementation of polytherapy, which was first established through the AMBITION trial with the dual combination of an ERA and a PDE5i. Additionally, this will markedly expand the prostacyclin class’s potential by encouraging first-line uptake alongside Opsumit, which is a market leader.
• Historically, ERAs have been the most commercially lucrative class; however, prostacyclins have now succeeded them, with total sales of $2.4bn versus $2.0bn for ERAs in 2020. Datamonitor Healthcare anticipates that the gap between prostacyclins and ERAs will widen further over the forecast period as ERAs are under rising threat from both generics and the increasing trend of prostacyclin use in triple combination therapies.
• The PDE5i class, which traditionally held a significant portion of market share, has faced fierce generic competition, with both Adcirca and Revatio being subject to generic erosion since 2018. A loss of market share held by PDE5is, from $814m in 2018 to $298m in 2019, was largely attributable to this generic competition. Revenue from PDE5is continued to decline in 2020, with Adcirca sales dropping to $119m, while Revatio sales are no longer reported by Pfizer.
• The guanylyl cyclase stimulator (GCS) class, which consists of a single asset, Adempas, is holding steady by stealing market share from the PDE5i class; however, this is limited to a minority of patients who respond poorly to PDE5is.
• Johnson & Johnson’s two newer marketed brands, Opsumit and Uptravi, are projected to become the highest-selling products during the forecast period. Opsumit is the established market leader, with blockbuster sales of $1.6bn in 2020. These two products will experience strong uptake, benefiting from physician familiarity, strong positioning in treatment guidelines, and robust efficacy data to support them. Importantly, Johnson & Johnson has generated efficacy data for morbidity/mortality, broadening the evidence base for its products. Although the results of the TRITON trial were largely negative, the triple combination therapy exhibited a numerical reduction in the risk of first disease progression event. In addition, overall mortality, an exploratory endpoint of the trial, was favorably lower in the triple combination arm, though this did not reach statistical significance. Additional studies are required to provide evidence for improved morbidity/mortality outcomes, and this would enable Uptravi to extend its reach to WHO FC II and III patients.
• Despite PAH patients making up only 20% of the PH population, most therapies are targeted at this group, with off-label use of drugs for groups 2, 3, and 5 PH. The high rate of off-label use highlights a critical unmet need for approved therapies in these indications. Increasing label expansions to include group 2–4 PH subtypes is a key area of interest and will be a major driver of growth in the PH market. Market leaders Opsumit and Uptravi are being investigated in clinical trials to potentially support label expansions to chronic thromboembolic pulmonary hypertension (CTEPH). This will bring new treatment options to underserved CTEPH patients who currently only have one approved therapy option, Adempas. The label expansion of United Therapeutics’ injectable treprostinil, Tyvaso, to include group 3 PH patients made it the first approved therapy for this subtype, enhancing the drug’s market potential in PH. Given the scarcity of competitors in non-PAH segments, there is a prominent opportunity for market penetration for these drugs.
• Approvals of pipeline candidates will diversify the PH market and meet an important unmet need to treat the underlying pathophysiology of the disease rather than just disease symptoms. Of the pipeline candidates in late-stage development, sotatercept, which targets the transforming growth factor beta (TGF-β) pathway to correct the underlying cause of the disease, is the most promising candidate and has been heralded as a game changer.
• Merck & Co’s $11.5bn acquisition of Acceleron is the second largest deal in the PH space thus far, behind only Johnson & Johnson’s acquisition of Actelion for its five-drug PH portfolio. Based on sotatercept’s potential to treat the underlying disease pathology and discussions with KOLs, Datamonitor Healthcare anticipates sotatercept to achieve mega-blockbuster sales, and therefore this is likely to be a lucrative opportunity for Merck & Co.
• Other notable pipeline candidates include United Therapeutics’ next-generation prostacyclin ralinepag, novel delivery systems such as INOpulse, and prodrugs for Orenitram and Remodulin – OreniPro and RemoPro, respectively. Datamonitor Healthcare predicts that pipeline candidates will have an initially muted effect on the market due to strong physician familiarity with the established brands and the static nature of the PH market.