Disease Analysis: Pulmonary Hypertension

Disease Overview

Pulmonary hypertension (PH) is a life-threatening and often fatal disease characterized by abnormal vascular proliferation and remodeling of the small pulmonary arteries and arterioles, vasoconstriction, and in situ thrombosis. This leads to a progressive increase in pulmonary vascular resistance (PVR) and, ultimately, the development of right ventricular (RV) dysfunction. Cornerstone histopathological features of the PH vasculopathy include intimal thickening, concentric hypertrophy, and perivascular fibrosis of distal pulmonary arterioles.

Report Highlights

• Pulmonary hypertension (PH) is a life-threatening and often fatal disease characterized by abnormal vascular proliferation and remodeling of the small pulmonary arteries and arterioles, vasoconstriction, and in situ thrombosis. This leads to a progressive increase in pulmonary vascular resistance (PVR) and, ultimately, the development of right ventricular (RV) dysfunction. There are five major clinical groups: pulmonary arterial hypertension (PAH); PH due to left heart disease; PH due to lung disease and/or hypoxia; chronic thromboembolic PH; and PH with unclear and/or multifactorial mechanisms.
• Datamonitor Healthcare expects the 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 functional class (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. The TRITON study, which investigated the use of a triple combination of Johnson & Johnson’s Opsumit (macitentan), an ERA, United Therapeutics’ Adcirca (tadalafil), a PDE5i, and Johnson & Johnson’s Uptravi (selexipag), a 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 could markedly expand the use of the prostacyclin class by encouraging first-line uptake alongside Opsumit, which is a market leader.
• Historically, ERAs were the most commercially lucrative class; however, prostacyclins have now overtaken them. Datamonitor Healthcare anticipates that sales from prostacyclins will continue to grow faster than ERAs 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 (sildenafil), from Viatris, being subject to generic erosion since 2018. Sales for PDE5is have fallen, largely due to this generic competition.
• 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, 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 showed 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 approved for this group. Off-label use of drugs for groups 2 and 5 PH has been observed, and to some extent in groups 3 and 4, where there is only one approved drug treatment. 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 PH, 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, therefore this is likely to be a lucrative opportunity for Merck & Co.
• Other notable pipeline candidates include United Therapeutics’ next-generation prostacyclin ralinepag, as well as Tenax Therapeutics’ re-evaluated candidates, including TNX-201 (imatinib) and Simdax (levosimendan). Datamonitor Healthcare expects 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