With the FDA closing out the month of November with three approvals in the last week – Vitrakvi (larotrectinib) from Bayer AG and Loxo Oncology Inc., Xospata (gilteritinib) from Astellas Pharma Inc. and Firdapse (amifampridine phosphate) from Catalyst Pharmaceuticals Inc. – the industry surpassed the high-water mark for the number of new molecular entities (NMEs) approved in one year in the U.S., previously set in 1996 when the agency approved 53 NMEs. (See BioWorld Insight, Jan. 8, 2018.)

Last week's spate of FDA nods brings the 2018 number to 55, with one month to go. However, all three of those recent approvals are targeting limited patient populations – specific mutations in acute myeloid leukemia and solid tumors for Xospata and Vitrakvi, respectively, and orphan disease Lambert-Eaton myasthenic syndrome in the case of Firdapse – meaning blockbuster potential will only be reached if firms opt for premium pricing. (Bayer has, setting the wholesale acquisition cost of Vitrakvi at $32,800 for a 30-day supply of 100-mg doses, or $393,600 per year. Astellas has set a wholesale acquisition cost for Xospata at $22,500 for a 30-day course of treatment, though consensus estimates are expecting modest sales of $82 million in 2020. And Catalyst has said it will disclose pricing for Firdapse during a Dec. 13 conference call, though the firm previously indicated a preference for premium orphan drug pricing.) (See BioWorld, Nov. 28, 2018, Nov. 29, 2018, and Nov. 30, 2018.)

But, overall, approved new drugs over the past decade have not been achieving blockbuster status with the frequency that they once did.

Increasing innovation

In the five-year period from 2013-2017, the sector achieved 181 NME approvals, compared to the 140 NMEs approved in the previous five-year period from 2008-2012. Yet only 12 percent (21) of those 181 new medicines have so far achieved annual sales that top $1 billion, according to a detailed analysis by BioWorld.

At one time, that would be seen as a negative for the sector whose business model in the 1980s and 90s was singly focused on developing blockbuster drugs. Back then, the formula for mega-blockbuster drugs was a pill a day for chronic diseases and conditions that affected a large portion of the population. Lipitor (atorvastatin), for instance, became the No. 1 bestselling drug by lowering cholesterol – in lots of people. The drug generated more than $130 billion in sales for Pfizer Inc., with peak annual sales of close to $13 billion. (See BioWorld Today, April 10, 2012.)

The golden age for mega-blockbusters has since been replaced by the development of more moderately selling drugs, some of which may reach close to or surpass the $1 billion peak annual sales threshold during their sales cycle before encountering generic competition when their patents expire. While there are still opportunities for high-volume drug sales, particularly in cancer and infectious viral disease indications, the industry's focus has shifted dramatically to embrace the development of medicines aimed at treating orphan and rare diseases, personalized and targeted medicines, and gene and cell therapies.

Over the last few years, large biopharmaceutical firms have certainly expanded beyond their traditional focus on major disease indications and plunged into rare diseases, pursuing collaborations, acquisitions and internal research initiatives in indications like Gaucher, Fabry and muscular dystrophy. As a result, since 2013, the number of orphan drug approvals has steadily increased to reach a record 59 in 2017. (See BioWorld, Jan 8, 2018.)

Top selling NMEs

Not surprisingly, approved cancer therapies occupy the leading positions in terms of annual sales of medicines that have been approved since 2013 and reached blockbuster status. (See Top 10-selling $1B+ NMEs approved since 2013, below.)

For example, the 2013 approval of Imbruvica (ibrutinib), the oral BTK inhibitor developed by Pharmacyclics Inc. and Johnson & Johnson unit Janssen Biotech Inc., as a single agent to treat patients with mantle cell lymphoma (MCL) who received at least one prior therapy, attained sales of $4 billion last year, good for the fourth spot on the top 10 leaderboard. Immuno-oncology drugs Opdivo (nivolumab, Bristol-Myers Squibb Co.) and Keytruda (pembrolizumab, Merck & Co. Inc.) have also achieved rapid blockbuster status. Opdivo tops the list currently. The drug gained FDA accelerated approval in December 2014 to treat patients with unresectable or metastatic melanoma who no longer responded to other drugs. Launched early in 2015, the PD-1 inhibitor achieved first-year blockbuster success with global sales of $1.117 billion. Its 2017 sales grew to $5.9 billion.

Holding down second position is Gilead Sciences Inc.'s Harvoni (sofosbuvir/ledipasvir), the first oral therapy for people with genotype 1 hepatitis C virus (HCV) to eliminate the need for both interferon and ribavirin, with 2017 sales of $4.4 billion. The once-daily pill, which also won approval in 2014, combines a dose of sofosbuvir, the active ingredient in Gilead's blockbuster HCV drug, Sovaldi, with ledipasvir, a direct-acting macrocyclic antiviral agent and an inhibitor of NS5A serine protease.

And, despite the crowded multiple sclerosis (MS) space, the 2013 FDA approval of Biogen Inc.'s Tecfidera (dimethyl fumarate) for relapsing forms of MS has certainly contributed nicely to its bottom line, with 2017 annual sales of $4.2 billion.

Positive projections

The BioWorld analysis showed that the projections for annual sales in 2023 of the NMEs approved since 2013, including the 52 approved as of Nov. 26, a further 49 medicines, or 23 percent, will reach the $1 billion mark. (See Top 10 NMEs approved since 2013, projected to be $1B+ by 2023, below.)

That would bring the total $1 billion-selling drugs by 2023 to 60 (30 percent) factoring in those that have already reached that mark.

Topping the list is Gilead's Biktarvy (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg, BIC/FTC/TAF), which was approved this year to treat HIV-1 infection in adults who have no antiretroviral treatment history. Sales of the once-daily medicine could reach as high as $6.2 billion in annual sales by 2023, according to Cortellis Competitive Intelligence data.

The widening pipeline focus of biopharma companies is evident with the approval of Acadia Pharmaceuticals Inc.'s Nuplazid (pimavanserin) to treat hallucinations and delusions associated with Parkinson's disease psychosis (PDP) and Neurocrine Biosciences Inc./Abbvie Inc.'s Orilissa (elagolix) to treat moderate to severe pain associated with endometriosis, both medicines projected to attain $1 billion-plus sales in the next five years.

It is interesting to note that of the 21 new medicines that have already achieved $1 billion in annual sales, by 2023, several are projected to grow dramatically. Keytruda, for instance, will reach sales of $17 billion annually – a true mega-blockbuster; Opdivo is projected to attain annual sales of $11 billion, and breakthrough therapy drug Ibrance (palbociclib, Pfizer Inc.), indicated for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, will grow to $8 billion in annual sales.