Despite fewer FDA approvals in 2015, the prospects for the API market in 2016 are strong.
Global demand for APIs is expected to increase at a compound annual growth rate (CAGR) of 6.5% from nearly $120 billion in 2013 to just under $186 billion in 2020, according to Transparency Market Research (1). APIs for drugs that treat cancer and central nervous system diseases will grow at the fastest rate, while those intended for the formulation of therapeutics for cardiovascular disease will account for the largest percentage of revenues. The growth of the oncology segment is driving demand for highly potent APIs (HPAPIs), which is predicted by Grand View Research to increase significantly from $12 billion in 2014 to $25.86 billion in 2022, which corresponds to an average annual growth rate of 14.4% (2).
Despite these positive predictions, it appears that the number of approvals of new molecular entity (NME) and biologic license application (BLE) approvals by FDA may be down in 2015. A total of 30 NME and BLA approvals were granted through Oct. 27, 2015 (3,4), while 41 new drugs were approved in 2014 (5). In 2013, 29 NMEs alone were approved (6). On the other hand, as established blockbusters-both small- and large-molecule-continue to lose patent protection, opportunities for generics and biosimilars, respectively, have increased. In particular, with an approval pathway for biosimilars now established in the United States, this segment of the API market is expected to experience dramatic growth. Market research firm RNCOS predicts that the formulated biosimilar market, which it estimates was worth $1.89 billion in 2014, will grow at a CAGR of 54.4% to reach $25.53 billion in 2020 (7).
Important firsts in 2015
The approval of the first biosimilar in the US in 2015 is a key event for the pharmaceutical industry. Zarxio, a biosimilar of Amgen’s Neupogen (filgrastim) received approval in March 2015 (8), but its launch was delayed until September 2015 due to a lawsuit filed by Amgen claiming lack of appropriate disclosure and patent negotiation on the part of developer Sandoz (the generic business of Novartis). Korea-based Celltrion is waiting on FDA’s decision regarding its biosimilar Remsima, which is a form of the rheumatoid arthritis drug Remicade (infliximab) marketed by Johnson & Johnson and Merck & Co. and is already approved in Europe.
FDA also made an approval decision with the potential to have significant impact on drug development and manufacturing when it approved the first 3D-printed drug in 2015 (9). Spritam (levetiracetam) is a rapid-dissolving tablet for the treatment of epileptic seizures based on a highly prescribed medicine. The product is manufactured by Aprecia Pharmaceuticals using its proprietary ZipDose additive manufacturing (3D printing) technology to produce porous tablets that disintegrate within seconds after the patient takes a sip of water. In addition, the company can produce customized doses containing 10 to 1000 milligrams of an active ingredient. The company expects to launch Spritam in the first quarter of 2016.
Accelerating drug development and approval
Much discussion within and outside of the pharmaceutical industry in 2015 focused on the need to accelerate the drug development and approval process to provide effective solutions for not only thousands of rare conditions with no current treatments, but also for major diseases that remain unaddressed. This issue was, in fact, one of few that the divided US House of Representatives agreed on. The 21st Century Cures bill was passed overwhelmingly in the House with a 344–77 vote and was supported nearly equally by Democrats and Republicans. In addition to calling for a further $8.75 billion in funding for the National Institutes of Health, the bill outlines measures for accelerating all aspects of the drug development and approval process, such as patient-focused drug development, modern approaches to clinical trial design, increasing communication and information exchange, improving manufacturing efficiencies, and the introduction of more pathways for accelerated approval by FDA.
There have, however, been questions raised about the increasing use of accelerated drug approval programs by FDA and the possible impact that such programs may have on the safety and efficacy of those drugs (10). The concern centers around the fact that accelerated approvals are often based on the results of smaller, early-phase trials with fewer patients and then expect manufacturers to develop additional post-market data. While these programs were initially intended for drugs that offered significant advances in treatment over existing drugs or new treatments for conditions that lacked any therapies, the majority of new drugs approved today are now associated with at least one of the four possible programs- fast track, accelerated approval, priority review, and orphan drug designation-with the result that many are likely not first-inclass or highly innovative (10).
Highlights of 2015 NME and BLA approvals
Of the 30 new molecular entities and biologic license applications approved by FDA through Oct. 27, 2015, 60% were NMEs and 14 (47%) had one or more accelerated approval designations. In line with the market data outlined above, the greatest numbers of new drug approvals were for oncology products and treatments related to cardiovascular diseases. Six drugs for the treatment of a variety of cancers (metastatic breast cancer), differentiated thyroid cancer, multiple myeloma, pediatric neuroblastoma, advanced local basal cell carcinoma (skin cancer), and advanced colorectal cancer were approved, three of which had one or more accelerated approval designations (11–16).
Unituxin (dinutuximab) from United Therapeutics is an antibody that binds to the surface of neuroblastoma cells and is the first approval of a therapy aimed specifically at the treatment of patients with high-risk neuroblastoma (14). Farydak (panobinostat) from Novartis Pharmaceuticals is effective for the treatment of multiple myeloma, a form of blood cancer that primarily affects older adults, and is the first histone deacetylase (HDAC) inhibitor approved for this indication (13). Farydak is used in combination with the chemotherapy agent bortezomib and the anti-inflammatory medication dexamethasone and operates by a mechanism different from that of existing therapies, which earned it an accelerated review and priority review in addition to orphan drug status.
Ibrance (palbociclib) from Pfizer for the treatment of advanced (metastatic) breast cancer earned a breakthrough therapy designation because preliminary clinical evidence suggested that the drug may offer a substantial improvement over available therapies (11). It works by inhibiting the cyclin-dependent kinases (CDKs) 4 and 6, which are known to promote the growth of cancer cells. Ibrance also received priority review and was approved under FDA’s accelerated approval program. A seventh drug, Varubi (rolapitant) from Tesaro, was also approved for the prevention of delayed phase chemotherapy- induced nausea and vomiting (17).
The second largest category of approvals includes six drugs for the treatment of ailments associated with cardiovascular disease. Savaysa (edoxaban) from Daiichi Sankyo (18) and Kengreal (canegrelor) from The Medicines Company (19) are designed to prevent blood clots. Amgen’s Corlanor (ivabradine) (20) and Novartis’ Entresto (sacubitril/ valsartan) (21) are for the treatment of heart failure. Both received priority review and fast-track designation.
Two drugs were also approved for the treatment of high cholesterol: Repatha (evolocumab) from Amgen (22) and Pratulent (alirocumab) from Sanofi-Aventis US and Regeneron Pharmaceuticals (23). These antibodies are the first members of a new class of injectable drugs known as PCSK9 inhibitors and work by preventing the PCSK9 protein from binding to receptors on the liver that remove LDL cholesterol from the blood.
Schizophrenia patients can look forward to three new possible treatments that were approved in 2015: Vralyar (cariprazine) from Forest Laboratories (distributed by Actavis Pharma) (24), Aristada (aripiprazole lauroxil) from Alkermes (25), and Rexulti (brexpiprazole) from Otuska Pharmaceutical Company (26).
The fifth and sixth antibiotics were also approved as Qualified Infectious Disease Products (QIDPs), a designation given to antibacterial or antifungal drug products that treat serious or lifethreatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. Cresemba (isavuconazonium sulfate) from Astellas Pharma is a new antifungal drug product used to treat adults with rare but serious invasive aspergillosis and invasive mucormycosis infections (27). Avycaz (ceftazidimeavibactam), distributed by Forest Pharmaceuticals, is a new antibacterial drug for the treatment of adults with complicated intra-abdominal and complicated urinary tract infections (28).
Several first treatments were also approved:
1. Transparency Market Research, “Global Active Pharmaceutical Ingredients (API) Market to Soar at 6.5% CAGR till 2020 Thanks to Rise in Abbreviated New Drug Applications (ANDAs),” Press Release, Oct. 1, 2015.
2. Grandview Research, “High Potency Active Pharmaceutical Ingredients (HPAPI) Market Worth $25.86 Billion by 2022,” Press Release, Oct. 1, 2015
3. FDA, “New Molecular Entity and New Therapeutic Biological Product Approvals for 2015,” accessed Oct. 27 2015.
4. FDA, “FDA approves new drug to treat hyperkalemia,” Press Release, Oct. 21, 2015.
5. FDA, “New Molecular Entity and New Therapeutic Biological Product Approvals for 2014,” accessed Oct. 27, 2015.
6. FDA, “New Molecular Entity Approvals for 2013,” accessed Oct. 27, 2015.
7. Reportlinker, “Global Biosimilar Market Outlook 2020-Reportlinker Review,” Press Release, Oct. 29, 2015.
8. FDA, “FDA approves first biosimilar product Zarxio,” Press Release, March 6, 2015.
9. Aprecia Pharmaceuticals, “FDA Approves the First 3D Printed Drug Product”, Press Release, Aug. 3, 2015.
10. A.S. Kesselheim et al. The BMJ, September 2015 DOI: 10.1136/bmj.h4633.
11. FDA, “FDA approves Ibrance for postmenopausal women with advanced breast cancer,” Press Release, Feb. 3, 2015.
12. FDA, “FDA approves Lenvima for a type of thyroid cancer,” Press Release, Feb. 13, 2015.
13. FDA, “FDA approves Farydak for treatment of multiple myeloma,” Press Release, Feb. 23, 2015.
14. FDA, “FDA approves first therapy for high-risk neuroblastoma,” Press Release, March 10, 2015.
15. FDA, “FDA approves new treatment for most common form of advanced skin cancer,” Press Release, July 24, 2015.
16. FDA, “FDA approves new oral medication to treat patients with advanced colorectal cancer,” Press Release, Sept. 22, 2015.
17. FDA, “FDA approves new drug treatment for nausea and vomiting from chemotherapy,” Press Release, Sept. 2, 2015.
18. FDA,” FDA approves anti-clotting drug Savaysa,” Press Release, Jan. 8, 2015.
19. FDA, “FDA approves new antiplatelet drug used during heart procedure,” Press Release, June 22, 2015.
20. FDA, “FDA approves Corlanor to treat heart failure,” Press Release, April 15, 2015.
21. FDA, “FDA approves new drug to treat heart failure,” Press Release, July 7, 2015.
22. FDA, “FDA approves Repatha to treat certain patients with high cholesterol,” Press Release, Aug. 27, 2015.
23. FDA, “FDA approves Praluent to treat certain patients with high cholesterol,” Press Release, July 24, 2015.
24. FDA, “FDA approves new drug to treat schizophrenia and bipolar disorder,” Press Release, Sept. 17, 2015.
25. FDA, “FDA approves new injectable drug to treat schizophrenia,” Press Release, Oct. 6, 2015.
26. FDA, “FDA approves new drug to treat schizophrenia and as an add on to an antidepressant to treat major depressive disorder,” Press Release, July 13, 2015.
27. FDA, “FDA approves new antifungal drug Cresemba,” Press Release, March 6, 2015.
28. FDA, “FDA approves new antibacterial drug Avycaz”, Press release, Feb. 25, 2015.
29. FDA, “FDA approves new treatment for cystic fibrosis,” Press Release, July 2, 2015.
30. FDA, “FDA approves new orphan drug to treat rare autosomal recessive disorder,” Press Release, Sept. 4, 2015.
31. FDA, “FDA approves first treatment for sexual desire disorder,” Press Release, Aug. 18, 2015.
32. FDA, “FDA approves new treatment for chronic hepatitis C genotype 3 infections,” Press Release, July 24, 2015.
33. FDA, “FDA approves Cholbam to treat rare bile acid synthesis disorders,” Press Release, March 17, 2015.