The US Food and Drug Administration (FDA) has approved 27 new molecular entities thus far in 2015, with five NME approvals just in the last month. In the all-important race for commercialization, what are top contenders and what may be expected of 2015? DCAT Value Chain Insights (VCI) takes an inside look.

As we approach the last quarter of 2015, the FDA’s Center for Drug Evaluation and Research has approved 27 new molecular entities (NMEs), which is on par with last year’s pace when the FDA approved 41 NMEs. DCAT Value Chain Insights (VCI) examines which companies have fared the best and which new drugs the leading pharmaceutical companies are banking on the most. 

NME watch: the year in review thus far 
Although drug approvals do not follow a chronological path and the end of the year often brings a wave of new approvals, the 27 NMEs approved thus far (as of September 29, 2015) is consistent with last year's pace when 29 NMEs had been approved by the end of September. This September, alone, has been a busy month with five NME approvals by the FDA: Novo Nordisk's Tresiba (insulin degludec injection) for improving blood sugar (glucose) control in adults with diabetes mellitus; Taiho Oncology's Lonsurf (trifluridine and tipiracil) for treating advanced colorectal cancer; Allergan's Forest Laboratories' Vraylar (cariprazine) for treating schizophrenia and bipolar disorder in adults; Wellstat Therapeutics' Xuriden (uridine triacetate) for treating hereditary orotic aciduria, a rare metabolic disorder; and Tesaro's Varubi (rolapitant) to prevent delayed phase chemotherapy-induced nausea and vomiting.

Table I outlines the 27 NMEs approvals thus far in 2015. Of the 27 NMEs approved thus far, 21 are small molecules (new drug applications (NDAs)), one is an insulin analogue approved as a NDA and five are biologics (biologics license applications (BLAs) (see Table I). The small-molecule approvals thus far in 2015 are: Allergan's (formerly Actavis) Viberzi (eluxadoline), Avycaz (ceftazidime-avibactam), and Vraylar (cariprazine); Amgen's Corlanor (ivabradine); Asklepion Pharmaceuticals/Retrophin's Cholbam (cholic acid); Astellas Pharma's Cresemba (isavuconazonium); Bristol-Myers Squibb’s Daklinza (daclatasvir); Daiichi Sankyo's Savaysa (edoxaban); Eisai’s Lenvima (lenvatinib); Kythera Biopharmaceuticals' Kybella (deoxycholic acid) (Kythera was later acquired by Allergan); Novartis' Farydak (panobinostat), Odomzo (sonidegib), and Entresto (sacubitril/valsartan); Pfizer's Ibrance (palbociclib); Otsuka Pharmaceutical’s Rexulti (brexpiprazole); Sprout Pharmaceuticals’ Addyi (flibanserin) (Allergan is acquiring Sprout Pharmaceuticals); Taiho Oncology’s Lonsurf (trifluridine and tipiracil); Tesaro’s Varubi (rolapitant); The Medicines Company's Kengreal (cangrelor); Vertex Pharmaceuticals’ Orkambi (lumacaftor and ivacaftor); and Wellstat Therapeutics’ Xuriden (uridine triacetate).

Six biologics have been approved thus far in 2015: Amgen’s Repatha (evolocumab); Novartis' Cosentyx (secukinumab); Tresiba (insulin degludec injection), a long-acting basal human insulin analog produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification (it was approved as a NDA and not as a BLA); Sanofi/Regeneron Pharmaceuticals’ Praluent (alirocumab); Shire/NPS Pharmaceuticals' Natpara (parathyroid hormone); and United Therapeutics' Unituxin (dinutuximab)

So how do the 27 NMEs approved in thus far in 2015 compared with previous years? The FDA's CDER approved 41 NMEs in 2014, 30 NDAs (i.e., small molecules) and 11 BLAs (i.e., biologics), both recent highs in terms of overall NME approvals and the number of approvals of new biologics by CDER. In comparison, FDA's CDER approved 27 NMEs in 2013 and 39 NMEs in 2012. From 2005 to 2013, CDER averaged 25 NME approvals per year, which was bolstered by approval levels in 2004 (36 NMEs approved), 2011 (30 NMEs approved), 2012 (39 NMEs approved), and 2013 (27 NMEs approved). The period of 2005 to 2010 was a slower period for NME approvals. In 2005, 20 NMEs were approved, 22 in 2006, 18 in 2007, 24 in 2008, 26 in 2009, and 21 in 2010. Of the 172 NMEs approved over the past five years (2010 to 2015 to June 30, 2015), 137 or 80% were small molecules, and 35 or 20% were biologics. Table II summarizes NME approvals for small molecules and biologics.over the past five years (2010 to 2015 to date).

Novartis and Allergan lead the pack
Among the large pharmaceutical companies, Novartis and Allergan are the leaders in terms of NME approvals thus far in 2015. Novartis has had four NME approved: Cosentyx (secukinumab) for treating moderate-to-severe plaque psoriasis,;Farydak (panobinostat) for treating multiple myeloma; for treating Odomzo (sonidegib) for treating locally advanced basal cell carcinoma (i.e., skin cancer); and Entresto (sacubitril/valsartan) for treating chronic heart failure;

Novartis points to high growth potential for Cosentyx (secukinumab), which was approved in the US and Europe in January 2015. Industry analysts are also bullish on Cosentyx as a potential blockbuster. A recent Thomson Reuters analysis estimates 2019 sales for Cosentyx at nearly $1.1 billion. Novartis is even more bullish, offering peak sales potential based on approval of additional indications in psoriasis and arthritis indications of $4 billion to $5 billion.

Secukinumab is an antibody that binds to a protein (interleukin (IL)-17A), which is involved in inflammation. By binding to IL-17A, secukinumab prevents it from binding to its receptor, and inhibits its ability to trigger the inflammatory response that plays a role in the development of plaque psoriasis. In addition to the US and EU, Cosentyx has been approved in Switzerland, Chile, Australia, Canada, and Singapore for the treatment of moderate-to-severe plaque psoriasis and in Japan for the treatment of moderate-to-severe plaque psoriasis and active psoriatic arthritis. Cosentyx is also in Phase III development for psoriatic arthritis and ankylosing spondylitis with regulatory applications made for the US and EU. Novartis said that is expects an opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use in the first half of 2016 and potential approval by the FDA in the second half of 2016 for these indications. Overall, Novartis said that Cosentyx is expected to be a blockbuster and that a scenario where it could reach peak sales of $4 billion to $5 billion in psoriasis and arthritis indications is possible.

Novartis' Entresto (sacubitril and valsartan) for treating chronic heart failure is another potential blockbuster for Novartis, which received US approval in 2015 with regulatory review pending in the European Union. A recent Thomson Reuters analysis estimates 2019 sales for Entresto at $3.7 billion. Entresto is an ARNI (angiotensin receptor neprilysin inhibitor) and has a mode of action that is thought to reduce the strain on the failing heart. It harnesses the body’s natural defenses against heart failure, simultaneously acting to enhance the levels of natriuretic and other endogenous vasoactive peptides while also inhibiting the renin-angiotensin-aldosterone system (RAAS).

Novartis' Farydak (panobinostat) for treating multiple myeloma and Odomzo (sonidegib) for treating locally advanced basal cell carcinoma are latest products in the company's oncology portfolio, which Novartis recently bolstered with its acquisition of the oncology assets of GlaxoSmithKline (GSK). The acquisition of GSK's oncology assets strengthened Novartis’ position in hematology, breast cancer, and renal cell carcinoma and provided Novartis with key assets in melanoma. Novartis acquired GSK’s oncology products, including two pipeline candidates, for an aggregate cash consideration of $16 billion. Up to $1.5 billion of this amount is contingent on certain development milestones. With the closing of the deal, Novartis’ oncology portfolio now includes 22 oncology and hematology medicines to treat more than 25 conditions. Some key products from GSK’s acquisition include: Tafinlar (dabrafenib), a BRAF inhibitor, and Mekinist (trametinib), a MEK inhibitor, both approved for the treatment of metastatic melanoma; Votrient, a VEGFR inhibitor for treating renal cell carcinoma; Promacta (eltrombopag) for treating thrombocytopenia; Tykerb (pazopanib) for treating HER2+ metastatic breast cancer; and Arzerra (ofatumumab) for treating chronic lymphocytic leukemia. Sales of the acquired GSK oncology products in 2014 were approximately $2.0 billion. In oncology, Novartis estimates that it is the number two player globally following the acquisition of the GSK oncology assets combined with the company's existing portfolio and pipeline. Novartis’ oncology position is built around targeted therapies, immuno-oncology assets, and chimeric antigen receptors T cells (CART) as both monotherapies and combination therapies.

Allergan (formerly Actavis) matches Novartis’ NME strength with three NME approvals and another NME to be gained from its pending $2.1 billion acquisition of Kythera Biopharmaceuticals. Through Forest Laboratories, which Allergan acquired in 2014 for $28 billion, Allergan received FDA approval this year for Vraylar (cariprazine) for treating schizophrenia and bipolar disorder in adults. Allergan also gained two additional NME approvals in 2015: Viberzi (eluxadoline) for treating irritable bowel syndrome with diarrhea and Avycaz (ceftazidime-avibactam) for treating adults with complicated intra-abdominal infections, in combination with metronidazole, and complicated urinary tract infections, including kidney infections (pyelonephritis). Avycaz is a fixed-combination drug containing ceftazidime, a previously approved cehalosporin antibacterial drug, and avibactam, a new beta-lactamase inhibitor. Avycaz was the fifth approved antibacterial drug product designated as a Qualified Infectious Disease Product (QIDP). This designation is given to antibacterial products to treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act.

Allergan is poised to pick up another NME in 2015 through its pending $2.1 billion acquisition of Kythera Biopharmaceuticals, a deal which Allergan announced in June 2015 and which is expected to close later this year. With the close of the deal, Allergan will gain Kythera's 2015 NME, Kybella (deoxycholic acid), which is used to treat moderate-to-severe fat below the chin or commonly known as double chin.

More NMEs with blockbuster potential
Among the large pharmaceutical companies, Amgen and Sanofi both scored NME approvals by the FDA for a new class of anti-cholesterol drugs, human monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver’s ability to remove low-density lipoprotein cholesterol (LDL-C), or “bad” cholesterol, from the blood. Amgen’s Repatha (evolocumab) and Sanofi’s/Regeneron’s Praluent (alirocumab) are pegged as potential blockbusters. Based on estimates for 2019 sales, a recent Thomson Reuters analysis puts potential revenues at Regeneron Pharmaceuticals and Sanofi's Praluent (alirocumab) at $4.4 billion, and Amgen's’ evolocumab at nearly $1.9 billion by 2019. In addition to receiving US approval, both drugs have been approved in the European Union.

Pfizer and Otsuka Pharmaceutical also received approval for drugs with blockbuster potential. Otsuka received FDA approval for Rexulti (brexpiprazole), an psychotropic compound discovered by Otsuka and co-developed with Lundbeck, for treating adults with schizophrenia and as an add-on treatment to an antidepressant medication to treat adults with major depressive disorder. The Thomson Reuters analysis estimates potential 2019 sales of $1.35 billion. Pfizer’s Ibrance (palbociclib), a drug to treat advanced (metastatic) breast cancer, is expected to be a strong performer for Pfizer, with the Thomson Reuters analysis offering 2019 sales estimates of $2.756 billion. Ibrance is a kinase inhibitor indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

Other NME approvals
In addition to its approval for Repatha, Amgen has had one other NME approval thus far in 2015: Corlanor (ivabradine), which is for reducing hospitalization from worsening heart failure. Corlanor is a hyperpolarization-activated cyclic nucleotide-gated channel blocker approved for use in certain people who have long-lasting (chronic) heart failure caused by the lower-left part of their heart not contracting well. The drug is indicated for patients who have symptoms of heart failure that are stable, a normal heartbeat with a resting heart rate of at least 70 beats per minute, and are also taking beta blockers at the highest dose they can tolerate. The European Medicines Agency approved the drug in 2005 to treat stable angina and then approved it in 2012 to treat chronic heart failure.

Among the other large pharma companies, Shire (through its acquisition of NPS Pharmaceuticals), Astellas Pharma, Daiichi Sanyko, and Eisai each have had one NME approved thus far in 2015. Through its $5.2 billion acquisition of NPS earlier this year, Shire gained the FDA-approved NME, Natpara (parathyroid hormone), for controlling hypocalcemia (low blood calcium levels) in patients with hypoparathyroidism, a rare endocrine disorder characterized by insufficient levels of the parathyroid hormone.

Astellas Pharma received FDA approval for Cresemba (isavuconazonium), a new antifungal drug product used to treat adults with invasive aspergillosis and invasive mucormycosis, rare but serious infections. Aspergillosis is a fungal infection caused by the Aspergillus species, and mucormycosis is caused by the Mucorales fungi. These infections occur most often in people with weakened immune systems. Cresemba belongs to a class of drugs called azole antifungal agents, which target the cell membrane of a fungus. Cresemba is the sixth approved antibacterial or antifungal drug product designated as a QIDP and the second in 2015 following the approval of Allergan's Avycaz (ceftazidime-avibactam). As part of its QIDP designation, Cresemba was given priority review, which provides an expedited review of the drug's application. The QIDP designation also qualifies Cresemba for an additional five years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act. As these types of fungal infections are rare, the FDA also granted Cresemba orphan drug designations for invasive aspergillosis and invasive mucormycosis.

Eisai received FDA approval for Lenvima (lenvatinib) for treating progressive, differentiated thyroid cancer that has progressed despite receiving radioactive iodine therapy. Lenvima is a kinase inhibitor, which works by blocking certain proteins from helping cancer cells grow and divide. Daiichi Sankyo received approval for the anti-clotting drug, Savaysa (edoxaban tablets), to reduce the risk of stroke and dangerous blood clots (systemic embolism) in patients with atrial fibrillation that is not caused by a heart valve problem. Savaysa was also approved to treat deep vein thrombosis and pulmonary embolism in patients who have already been treated with an anti-clotting drug administered by injection or infusion (parenterally), for five to ten days.

Through its pending $1 billion acquisition of Sprout Pharmaceuticals, Valeant Pharmaceuticals International, Inc. will gain a NME, Addyi (flibanserin), to treat acquired, generalized hypoactive sexual desire disorder in premenopausal women. The deal, announced in August 2015, is expected to close later this year. Under terms of the acquisition agreement, Valeant will pay approximately $500 million, subject to customary purchase price adjustments, upon the closing of the transaction and an additional payment in the amount of $500 million, payable in the first quarter of 2016, plus a share of future profits based upon the achievement of certain milestones.

In other drug approvals, The Medicines Company received approval for Kengreal (cangrelor), an intravenous antiplatelet drug that prevents formation of harmful blood clots in the coronary arteries, the blood vessels that supply blood to the heart. It is approved for adult patients undergoing percutaneous coronary intervention, a procedure used to open a blocked or narrowed coronary artery to improve blood flow to the heart muscle.

There have several NME approvals in 2014 for orphan or rare diseases, Asklepion Pharmaceuticals received approval for Cholbam (cholic acid) capsules for treating pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects, and for patients with peroxisomal disorders (including Zellweger spectrum disorders). Patients with these rare, genetic, metabolic conditions exhibit manifestations of liver disease, steatorrhea (presence of fat in the stool), and complications from decreased fat-soluble vitamin absorption. Individuals with these rare disorders lack the enzymes needed to synthesize cholic acid, a primary bile acid normally produced in the liver from cholesterol.

With the FDA approval of Cholbam in March 2015, the biopharmaceutical company, Retrophin, exercised its right to purchase from Asklepion all worldwide rights, titles, and ownership of Cholbam and related assets. Retrophin paid Asklepion a one-time cash payment of $27 million, in addition to approximately 661,278 shares of Retrophin common stock (initially valued at $9 million at the time of the announced agreement in January 2015), which assumed Cholbam received an approval for a CTX indication. Asklepion will also be eligible to receive up to $37 million in cumulative sales milestones, as well as tiered royalties based on future net sales of Cholbam. With the approval of Choblam, the FDA also granted Asklepion a Rare Pediatric Disease Priority Review Voucher (Pediatric PRV), a provision that encourages development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. This voucher is designed to be transferable or sold and provides the bearer with an expedited FDA review for any new drug application. The Pediatric PRV was transferred to Retrophin under the original terms of the agreement with Asklepion. In May 2015, Retrophin agreed to sell the pediatric voucher to Sanofi for $245 million ($150 million upfront followed by two equal installments of $47.5 million in 2016 and 2017).

This was the second time that Sanofi has purchased a pediatric PRV. In 2014, Sanofi and Regeneron Pharmaceuticals purchased a pediatric PRV from BioMarin GALNS Ltd., a direct, wholly owned subsidiary of BioMarin Pharmaceutical, Inc., which had received it through the FDA's Rare Pediatric Disease Priority Review Voucher Program and the 2014 approval of BioMarin's Vimizim (elosulfase alfa) for treating Mucopolysaccharidosis Type IVA (Morquio A syndrome). Sanofi and Regeneron equally shared the purchase price of PRV $67.5 million. Sanofi and Regeneron had purchased it for their BLA submission for alirocumab, is an investigational monoclonal antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), which is being evaluated for its potential to lower low-density lipoprotein cholesterol (LDL-C) in patients who are not at their current LDL-C target with standard lipid-modifying therapies. The priority review voucher entitles the holder to designate a BLA for priority review, which provides for an expedited 6-month review from the filing date instead of the standard 10-month review.

Wellstate Therapeutics’ Xuriden (uridine triacetate) was approved for treating hereditary orotic aciduria, a rare metabolic disorder, which has been reported in approximately 20 patients worldwide. Xuriden was granted a rare pediatric disease priority review voucher. In September 2014, Wellstat entered into an agreement with AstraZeneca under which the Pediatric Priority Review Voucher would be transferred to AstraZeneca upon approval. Financial terms of the agreement were disclosed.