Looking back at 2015, which potential blockbusters have made the mark and remain poised for commercial success? DCAT Value Chain Insights (VCI) takes an inside look.

A Thomson Reuters analysis pointed to 11 potential blockbusters entering the market or being approved in 2015. Of these 11 drugs, all are still positioned to exceed sales of $1 billion by 2019. So which drugs are the winners from 2015?

By Ulrike Jahnke, Thomson Reuters, London

Future blockbusters approved in 2015
In early 2015, Thomson Reuters Cortellis Competitive Intelligence predicted in the Drugs To Watch report that more potential blockbusters would enter the market in 2015 than in 2014, with the anticipated approval/entry of 11 drugs in 2015 (versus three drugs in 2014) with sales forecast to exceed $1 billion in 2019. As it turns out, all of the predicted drugs plus some more were approved and/or entered the market in 2015, and all are expected to be blockbuster drugs five years from now. So which drugs made the mark?

While Bristol-Myers Squibb’s (BMS) Opdivo (nivolumab) for melanoma, non-small-cell lung cancer (NSCLC) and renal cell carcinoma (RCC) is still top of the list, with $8.887 billion in sales forecast for 2019, forecasts of the other blockbusters have fluctuated (see Table I). In early 2015, sales of more than $4 billion were anticipated for Regeneron Pharmaceuticals and Sanofi’s Praluent (alirocumab) for hypercholesterolemia, putting it in second place, but this has now been reduced to $1.957 billion (with a projected ranking of seventh). However, sales of Pfizer’s Ibrance (palbociclib) for breast cancer have risen from $2.756 billion to $4.598 billion, rising in the ranks from fourth to second, and similarly, sales of Vertex Pharmaceutical’s Orkambi (lumacaftor plus ivacaftor) for cystic fibrosis have increased from $2.737 billion to $3.549 billion, rising from fifth to third, closely followed by Novartis’ Entresto (sacubitril and valsartan) for chronic heart failure for which sales of $3.429 billion are forecast for 2019, slightly decreasing from $3.731 billion and rising from third to fourth place (see Table 1).

Other predicted blockbusters include Amgen and Astellas Pharma’s Repatha (evolocumab) for hypercholesterolemia, with projected 2019 sales of $1.994 billion, rising in ranks from seventh to fifth, Novartis’ Cosentyx (secukinumab) for psoriasis and psoriatic arthritis with projected 2019 sales of $1.986 billion, rising from eleventh to sixth place, and AbbVie’s Viekira Pak (paritaprevir, ritonavir, ombitasvir and dasabuvir) for hepatitis C virus (HCV) with 2019 projected sales of $1.791 billion and declining a bit from sixth to eighth place (see Table I). Other projected blockbusters include Sanofi’s Toujeo (new formulation of insulin glargine) for diabetes, $1.299 billion in projected sales, inching up from tenth to ninth place, and Otsuka Pharmaceutical’s and Lundbeck’s Rexulti (brexpiprazole) for schizophrenia and depression with 2019 projected sales of $1.092 billion, rising in ranks from ninth to tenth place. Forecasts for Merck & Co’s Gardasil 9 vaccine against human papillomavirus infection (ranked eighth) were not available as of February 2016.

Not predicted in the Drugs To Watch to have billion-dollar sales in 2019 are three treatments for multiple myeloma: Janssen’s Darzalex (daratumumab; $1.981 billion), BMS’ and AbbVie’s Empliciti (elotuzumab; $1.127 billion), and Takeda’s Ninlaro (ixazomib citrate; $1.012 billion). Predicted sales of all these drugs are expected to continue to rise in 2020 (apart from Viekira Pak).

Opdivo now also approved for NSCLC and RCC
Opdivo continues to lead in the immuno-oncology field and not only saw additional approvals for melanoma but also for NSCLC and RCC. For previously untreated BRAF V600 wild-type unresectable or metastatic melanoma patients, Opdivo was approved in the US in October 2015 for combination use with Yervoy (ipilimumab) and as a single agent in November 2015. Approval was also granted for previously treated metastatic squamous (approved in March 2015) and non-squamous NSCLC (approved in October 2015) based on superior overall survival versus standard of care. The CheckMate-017 and CheckMate-057 studies in metastatic squamous and non-squamous refractory NSCLC patients, respectively, showed a 41% and 27% reduction in the risk of death, respectively. Importantly, Opdivo is not limited to second-line patients testing positive for PD-L1, unlike Merck & Co’s PD-1 inhibitor Keytruda (pembrolizumab), which although approved ahead of Opdivo for both squamous and non-squamous NSCLC in early October 2015, is likely to see fewer sales due to a restricted patient population. Furthermore, Opdivo’s patient population was further expanded with the November 2015 approval as the first and only PD-1 inhibitor to deliver significant overall survival in patients with previously treated advanced RCC, with the CheckMate-025 trial showing median overall survival of 25 versus 19.6 months for the current standard of care Afinitor (everolimus). Further indications are likely, such as glioblastoma, hepatocellular carcinoma, and SCLC, and while in early 2015, 2019 forecasts were $5.684 billion, as of February 2016, they have increased to $8.887 billion for 2019 and further to $10.677 billion for 2020. Direct competitor Keytruda is forecast to have 2020 sales of $5.119 billion.

Potential expanded breast cancer indication for IbranceC
At the time of the Drugs To Watch report in early 2015, Pfizer’s first-in-class CDK4 and 6 inhibitor, Ibrance (in combination with aromatase inhibitor letrozole), had been launched immediately following accelerated approval in February 2015 for postmenopausal women with ER+ HER2- advanced breast cancer based on Phase II data from the PALOMA-1 trial, and 2019 sales were forecast at $2.756 billion. Since that time, topline data from the first phase III, PALOMA-3 trial have been released showing that median progression-free survival was improved by 5.4 months with Ibrance plus fulvestrant relative to placebo plus fulvestrant in patients with ER+ HER2- advanced breast cancer who had relapsed or progressed during prior endocrine therapy, regardless of menopausal status. An supplemental new drug application was subsequently submitted in December 2015, and approval could substantially expand Ibrance’s indication; a similar filing was submitted in the European Union (EU) in August 2015. Forecasts for Ibrance have now increased to $4.598 billion for 2019 and further to $4.807 billion for 2020.

Entresto approval revives heart failure market
In July 2015, the US Food and Drug Administration (FDA) approved Novartis’ Entresto, which combines the enhancement of cardioprotective mechanisms via neprilysin inhibition (sacubitril) with the antihypertensive effects of angiotensin antagonism (valsartan). Approval in the US was followed by EU approval in November 2015 and was based on strong data from the PARADIGM-HF trial which demonstrated reductions in the risk of cardiovascular death (by 20%), the risk of hospitalization for heart failure (by 21%) and all cause-mortality (by 16%) compared with enalapril. Entresto meets a significantly unmet need for a disease that leads to death in 50% of patients within five years of diagnosis. The lack of approved therapies to reduce risk of death contribute to Entresto’s blockbuster potential. In early 2015, forecasts for 2019 were $3.731 billion, which following a slow roll-out hampered by formulary blocks has decreased to $3.429 billion for 2019 as of February 2016, but with anticipated better payer coverage, sales is expected to increase to $4.337 billion for 2020.

Orkambi taps into largest cystic fibrosis market
In July 2015, Vertex’s Orkambi became the first drug to target the underlying cause of cystic fibrosis in people with two copies of the F508del mutation. The FDA approved Orkambi for patients aged 12 years and older based on the TRAFFIC and TRANSPORT studies. The European Medicines Agency (EMA) took the same steps and approved Orkambi in November 2015. The F508del mutation is the most common cystic fibrosis mutation, and with no other current curative treatment option, Vertex is set to reap significant benefits from Orkambi with 2019 forecast sales of $3.549 billion (up from $2.737 billion in early 2015), reaching $4.254 billion in 2020.

Narrow labels for PCSK9 inhibitors Praluent and Repatha
In the race to become the next cholesterol-lowering blockbuster, Regeneron and Sanofi’s Praluent became the first to be approved in the US and Astellas’ Repatha the first to be approved in the EU, both in July 2015; EU approval for Praluent followed in September 2015 and US approval for Repatha in October 2015. However, while approval for both Praluent and Repatha was anticipated for the broad indication of primary hypercholesterolemia, the FDA limited both drugs to a subset of patients predisposed to high cholesterolemia at the limit of their statin therapy, greatly limiting the potential target population. Cardiovascular outcomes studies are ongoing for both Praluent and Repatha and could ultimately broaden the patient population, but current 2019 forecasts are lower (although undoubtedly still blockbusters) than in early 2015 for Praluent ($1.957 billion versus $4.414 billion) and similar for Repatha ($1.994 billion versus $1.862 billion), rising to $2.500 billion and $2.461 billion, respectively, in 2020.

Viekira associated with serious liver injury risk
Of the blockbusters discussed in the Drugs To Watch, the only one for which forecasts to 2020 are decreasing relative to 2019 is AbbVie’s all-oral interferon-free HCV regimen Viekira Pak, a combination of the NS3/4A protease inhibitor paritaprevir (formerly veruprevir), the boosting agent ritonavir, and the NS5A inhibitor ombitasvir, coformulated and dosed alongside the NS5B polymerase inhibitor dasabuvir. Viekira Pak with or without ribavirin was launched in the US and EU in January 2015 for HCV genotype 1, and in the EU with ribavirin for HCV genotype 4, following approvals in December 2014 and January 2015, respectively. The combination of paritaprevir, ritonavir and ombitasvir, with ribavirin, was additionally approved in the US as Technivie for HCV genotype 4 in July 2015. AbbVie’s HCV treatments requiring multiple pills per day directly compete with Gilead’s one-pill-per-day Harvoni and price-cut exclusivity deals with payers have played a major role in determining market share. However, bad news came for AbbVie in October 2015 when the FDA issued a warning that Viekira Pak and Technivie can cause serious liver injury in patients with underlying advanced liver disease, positioning Harvoni as a safer option for HCV. Additionally, a new competitor has just entered the market; Merck’s once-daily Zepatier (a fixed-dose combination of grazoprevir/elbasvir) was approved in January 2016 and is itself anticipated to become a blockbuster. Viekira Pak still has predicted blockbuster sales of $1.749 billion forecast for 2020, but these are slightly lower than the current 2019 forecasts of $1.791 billion, which in itself are lower than anticipated earlier in 2015 ($2.5 billion).

Approvals and market entry for Cosentyx, Toujeo and Rexulti
The year 2015 also saw the approval and market entry of the potential blockbusters Cosentyx, Novartis’ first-in-class IL-17A inhibitor for psoriasis and psoriatic arthritis; Toujeo, Sanofi’s more concentrated version of its insulin glargine product Lantus for type 1 and type 2 diabetes; and Rexulti, Otsuka and Lundbeck’s serotonin-dopamine activity modulator for major depressive disorder and schizophrenia. As of February 2016, predicted sales for 2019 were $1.986 billion for Cosentyx (was $1.082 billion), $1.299 billion for Toujeo (was $1.265 billion) and $1.091 billion for Rexulti (was $1.353 billion), all rising in 2020 to $2.381 billion, $1.522 billion and $1.788 billion, respectively.

Three novel potential blockbusters for multiple myeloma
Within a couple of weeks in November 2015, the FDA approved three new treatments for multiple myeloma, all several months earlier than ex¬pected and all for later-line therapy in this highly refractory disease. In mid-November 2015, Janssen’s Darzalex became the first approved human anti-CD38 monoclonal antibody, only months after a BLA was submitted in September 2015 for which a PDUFA date had been set for March 2016. The FDA approved Darzalex under accelerated approval for use in patients who have received at least three prior lines of therapy based on a response rate of 29.2% in the Phase II SIRIUS trial in patients who received a median of five prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

Approval of Darzalex was followed a few days later by approval of Takeda’s Ninlaro, the first oral proteasome inhibitor to be approved for multiple myeloma. Ninlaro is approved for use in combination with Revlimid and dexamethasone for patients who have received at least one prior therapy. A filing had been submitted in July 2015 with a PDUFA date set for March 2016, but reflecting the unmet need in multiple myeloma, the FDA approved Ninlaro 4 months early. Approval was based on data from the TOURMALINE-MM1 trial which demonstrated a 35% improvement in progression-free survival in relapsed/refractory multiple myeloma patients receiving Ninlaro plus Revlimid and dexamethasone compared with Revlimid and dexamethasone.

Just over a week after Ninlaro approval, the FDA approved BMS and AbbVie’s Empliciti for use in combination with Revlimid and dexamethasone in multiple myeloma patients who have received one to three prior therapies. Empliciti is the first and only immunostimulatory antibody for multiple myeloma and approval was based on the ELOQUENT-2 study which showed a 30% reduction in the risk of disease progression or death for Empliciti plus Revlimid and dexamethasone compared with Revlimid and dexamethasone alone. The BLA was submitted in September 2015. Although all three are approved for later-line therapy, blockbuster sales are predicted due to the fact that the majority of multiple myeloma patients will relapse or become resistant to earlier-line therapies. Forecasts for 2019 are $1.981 billion for Darzalex, $1.012 billion for Ninlaro and $1.127 billion for Empliciti, rising to $2.505 billion, $1.480 billion and $1.361 billion, respectively, in 2020.

In summary
As predicted in early 2015 by Thomson Reuters Cortellis Competitive Intelligence, 2015 was set to become a year to see the approval and market entry of a far greater number of potential blockbusters than 2014. All of the forecast agents plus some more have indeed been approved and launched, suggesting a continued appeal of the blockbuster model. Whether this continues into 2016 remains to be seen.

For potential blockbusters entering the market in 2016, see related article, “Blockbuster Watch: Key Market Entrants for 2016.”