Top Orphans Mirror Mainstream Drugs
The blurring lines between niche and non-orphan drugs are also evident elsewhere in the top ten roster as lifecycle management tactics and expanding awareness of less-prevalent diseases inflate orphan sales.
Vertex’s cystic fibrosis therapy Alyftrek will be the second-biggest orphan drug in 2030, with forecast sales of over $8 billion. Approved in December 2024, Alyftrek is a three-drug combo taken once-daily and thus more convenient than $10bn-a-year predecessor Trikafta (which, though declining, will still be the eleventh best-selling orphan in 2030). Alyftrek is Vertex’s fifth cystic fibrosis transmembrane conductance regulator (CTFR) modulator, and the latest in a suite of incrementally improved CTFR gene correctors and longer acting potentiators that have extended the biotech’s dominance in a disease area affecting fewer than 100,000 people worldwide. Vertex’s combined orphan sales will reach close to $15 billion in 2030.
The third-largest orphan drug by forecast 2030 sales is Winrevair (sotatercept) for pulmonary arterial hypertension (PAH). The condition - characterised by thickening of the arteries carrying blood from the heart to the lungs – affects fewer than 50,000 US individuals. Yet Winrevair is now a core driver of Merck’s cardiovascular franchise. Obtained through Merck’s $11.5 billion acquisition of Acceleron in 2021, Winrevair helps place the pharma firm eighth in the top ten companies by 2030 orphan drug sales, and fuels a 2025-2030 orphan sales CAGR of over 30%, more than three times that of any other top ten firm in the space. (See company top ten and growth rates, table below).
Winrevair builds on a script written by Swiss-based biotech Actelion in the fifteen years preceding its $30 billion acquisition by Johnson & Johnson in 2017. PAH was virtually unheard of before Actelion’s pioneer vasodilator Tracleer (bosentan) was launched in 2001, accompanied by a vigorous disease awareness campaign.
Today, like the rare blood cancers, PAH is a Big Pharma battleground. Winrevair faces J&J’s newly approved Opsynvi tablet combining Actelion legacy drug Opsumit (macitentan) with United Therapeutics’ Adcirca (tadalafil), a formulation of Lilly’s erectile dysfunction drug Cialis.
Amsterdam-based Argenx, meanwhile, is reading Big Pharma’s life cycle management playbook with a rare autoimmune diseases franchise built around Vyvgart (efgartigimod alfa). Vyvgart – forecast to be the tenth best-selling orphan in 2030, with sales approaching $4 billion – was first approved in the US in 2021 for myasthenia gravis (MG). The drug fell out of the top ten in 2028’s forecasts (see last year’s report), likely due to anticipated competition: two new MG drugs were approved in 2023 from mid-sized pharma UCB alone, and J&J’s pipeline star nipocalimab has been filed for the condition.
Yet a subcutaneous version of Vyvgart, made with hyaluronidase – the same approach deployed to extend the lives of Darzalex, Keytruda and others – is being lined up. Vyvgart Hytrulo was approved for MG in 2023 and got a second green light last year for chronic inflammatory demyelinating polyneuropathy (CIDP). (Combining Hytrulo and Vyvgart forecasts would place the franchise fourth, behind Winrevair, with $6.6 billion in 2030 sales). Active ingredient efgartigimod is in registrational trials in six other diseases, and in proof of concept testing for almost as many again.
