Pharma Industry on Track to Outpace New Drug Approvals in 2014
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The US Food and Drug Administration’s Center for Research and Evaluation has approved 26 new molecular entities thus far in 2014, only one short of the 27 approved in all of 2013. So will 2014 be a banner year for new drug approvals?

New drug approvals are an important barometer of the financial health of the overall pharmaceutical industry and for individual companies. This year is shaping up to be a good one with 26 new molecular entities (NMEs) approved thus far in 2014, only one shy of the 27 approved in all of 2013 (see Table I at end of article). But the total number of approvals is only one measure. How have the large pharmaceutical companies fared in new drug approvals and what is the competition for these new drugs? How do approvals for small molecules and biologics compare? DCAT Value Chain Insights takes an inside look.

Tracking the fortunes of Big Pharma
Of the 26 NMEs approved as of August 24, 2014, more than half, 14, are from the large pharmaceutical/biopharmaceutical companies. AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Merck & Co. each had two NME approvals, and Biogen Idec, Gilead Sciences, GlaxoSmithKline (GSK), Janssen Biotech (part of Johnson & Johnson), Novartis, and Takeda Pharmaceutical each had one.

AstraZeneca received FDA approval for its diabetes drug Farxiga (dapaglifozin) and the orphan drug Myalept (metreleptin), a recombinant analog (laboratory-created form) of human leptin as a replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy. Farxiga was approved by the FDA in January 2014. It was approved in Europe, where it is marketed as Forxiga, in November 2012 and in Japan in March 2014. Farxiga was the second drug approved by FDA in a new class of drugs to treat diabetes, sodium glucose cotransporter 2 (SGLT2) inhibitors. The first was Janssen Pharmaceuticals’ Invokana (canagliflozin), which was approved in 2013. As a SGLT2 inhibitor, Farxiga blocks the reabsorption of glucose by the kidney, increases glucose excretion, and lowers blood glucose levels. It indicated as an adjunct to diet and exercise as a once-daily oral medication to improve glycemic control in adult patients with Type 2 diabetes mellitus as an add-on combination therapy or as monotherapy in metformin-intolerant patients.

AstraZeneca gained full rights to Farxiga as well as Myalept as part of its $2.7-billion acquisition of its diabetes alliance with Bristol-Myers Squibb, a deal which was completed in February 2014. The acquisition gave AstraZeneca ownership of the intellectual property and global rights for the development, manufacture, and commercialization of the diabetes business, which included Farxiga/Forxiga, Xigduo (dapaglifozin and metformin HCl extended release), Onglyza (saxagliptin), Komboglyze (saxagliptin and metformin HCl), Kombiglyze XR (saxagliptin and Byetta (exenatide), Bydureon (exenatide extended-release for injectable suspension), metreleptin, and Symlin (pramlintide acetate). In addition to the $2.7-billion, AstraZeneca has also agreed to pay up to $1.4 billion in regulatory, launch, and sales payments, and various sales-related royalty payments up until 2025, $600 million of which relates to the approval of Farxiga in the US. In addition, AstraZeneca may make payments of up to $225 million when certain assets are subsequently transferred.

Boehringer Ingelheim and Eli Lilly received approval of their SGLT2 inhibitor, empagliflozin, in August 2014. The drug was developed as part of the diabetes alliance between Boehringer Ingelheim and Eli Lilly, which was formed in 2011. In March 2014, the FDA issued a Complete Response Letter for the companies’ new drug application (NDA) for empagliflozin. The Complete Response Letter referenced previously observed deficiencies at a Boehringer Ingelheim facility where empagliflozin will be manufactured. These deficiencies needed to be resolved before the approval of the application. In April 2014, the companies reported that the FDA had also accepted their NDA for a combination tablet of empagliflozin and linagliptin, Boehringer Ingelheim’s dipeptidyl peptidase-4 (DPP-4) inhibitor, for the treatment of adults with Type 2 diabetes. If granted approval by the FDA, the combination would provide the mechanisms of action of a SGLT2 inhibitor (empagliflozin) and a DPP-4 inhibitor, linagliptin.

Other pharmaceutical companies have late-stage SGLT2 inhibitors in development. Pfizer and Merck & Co. are developing their SGLT2 inhibitor, ertugliflozin, which is in Phase III trials. In April 2013, Pfizer and Merck formed a collaboration for the development and commercialization of Pfizer’s ertugliflozin. The companies are collaborating on the clinical development and commercialization of ertugliflozin and ertugliflozin-containing fixed-dose combinations with metformin and Merck’s Januvia (sitagliptin) tablets. Merck will continue to retain the rights to its existing portfolio of sitagliptin-containing products. Pfizer received an upfront payment and milestones of $60 million and will be eligible for additional payments associated with the achievement of pre-specified future clinical, regulatory, and commercial milestones. Merck and Pfizer will share potential revenues and certain costs on a 60/40% basis.

In January 2014, Astellas Pharma received marketing approval in Japan for its SGLT2 inhibitor Suglat (ipragliflozin L-proline). In April 2014, the Japanese pharmaceutical company Taisho Pharmaceutical received manufacturing and marketing approval in Japan for its SGLT2 inhibitor Lusefi (luseogliflozin) for treating Type II diabetes. Among smaller companies, Islet Sciences, a biopharmaceutical company based in Raleigh, North Carolina, announced a letter of intent to acquire BHV Pharma, based in Research Triangle Park, North Carolina, which is developing the SGLT2 inhibitor remogliflozin etabonate for the treatment of Type II diabetes. Lexicon Pharmaceuticals, Inc., based in Princeton, New Jersey, has an SGLT2 inhibitor, LX4211, in Phase II clinical trials.

Eli Lilly and Boehringer Ingelheim also received separate approvals for new drugs. Earlier this year, Eli Lilly gained FDA approval of an orphan drug, Cyramza (ramucirumab), to treat advanced stomach cancer or gastroesophageal junction adenocarcinoma. In July 2014, Boehringer Ingelheim received FDA approval for its respiratory drug, Striverdi Respimat (olodaterol) inhalation spray to treat patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema that are experiencing airflow obstruction. Boehringer Ingelheim is also studying olodaterol as a possible future combination partner with Spiriva (tiotropium bromide inhalation powder), the company’s long-acting muscarinic antagonist treating COPD. In May 2014, the company reported positive Phase III results of a once-daily fixed-dose combination of tiotropium and olodaterol. Both olodaterol as a monotherapy and the fixed-dose combination of tiotropium and olodaterol are delivered using Boehringer Ingelheim’s Respimat SoftMist Inhaler. Respimat is an inhaler delivering a slow-moving “soft mist” that is designed to allow gentle inhalation to make it easier for patients to take their therapy. In 2013, Boehringer Ingelheim increased production capacity for the Respimat inhaler at its facilities in Dortmund and Ingelheim, Germany, at a cost of EUR 57 million ($76 million), according to the company’s 2013 earnings release of April 15, 2014.

Merck & Co. has had two NMEs approvals thus far in 2014: Belsomra (suvorexant), a drug to treat insomnia, and the anti-platelet agent Zontivity (vorapaxar). Belsomra is an orexin receptor antagonist and is the first approved drug of this type. Orexins are chemicals that are involved in regulating the sleep-wake cycle and play a role in keeping people awake. Belsomra alters the signaling action of orexin in the brain. The FDA has recommended that Belsomra be classified by the US Drug Enforcement Administration (DEA) as a scheduled product. Earlier this year, the DEA proposed a Schedule IV drug classification under the Controlled Substances Act. The DEA has not yet issued a final decision on the scheduling for Belsomra, and, therefore, the product cannot become available before that decision. The drug is expected to be available in late 2014 or early 2015.

The other NME approval for Merck, Zontivity, is the first in a new class of drugs, called protease-activated receptor-1 (PAR-1) antagonists. It is designed to decrease the tendency of platelets to clump together to form a blood clot. By decreasing the formation of blood clots, Zontivity decreases the risk of heart attack and stroke. It was approved by the FDA to reduce the risk of heart attack, stroke, cardiovascular death, and the need for procedures to restore the blood flow to the heart in patients with a previous heart attack or blockages in the arteries to the legs.

Other drug approvals
GSK received approval for its diabetes drug Tanzeum (albiglutide) in April 2014. Albiglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist is a biological product for treating Type 2 diabetes, administered once-weekly using an injector pen. It is a recombinant fusion protein comprised of two tandem copies of modified human GLP-1 genetically fused in tandem to human albumin. Glucagon-like peptide-1 is an important incretin hormone that helps reduce blood glucose levels but, in people with Type 2 diabetes, its production is often reduced or absent, according to a GSK press release. GSK anticipates the US launch of Tanzeum in the third quarter of 2014. Albiglutide was licensed by the European Medicines Agency in March 2014 under the brand name Eperzan.

In gaining approval for Tanzeum, GSK will be competing against other GLP-1 agonists: AstraZeneca’s Byetta (exenatide injection) and Bydureon (exenatide extended-release injectable suspension) and Novo Nordisk’s Victoza (liraglutide). Sanofi’s Lyxumia (lixisenatide) was in-licensed from Zealand Pharma A/S and is approved in Europe for the treatment of adults with Type 2 diabetes mellitus to achieve glycemic control in combination with oral glucose-lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycemic control. Lyxumia is also approved in Mexico, Australia, Japan, and Brazil for the treatment of adults with Type 2 diabetes. Sanofi plans to resubmit the new drug application for lixisenatide in the United States in 2015 after completion of the ELIXA cardiovascular outcomes study.

Novartis received approved for its cancer drug Zykadia (ceritinib), designed to treat a certain type of metastatic non-small cell lung cancer. Zykadia is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that blocks proteins that promote the development of cancerous cells. It is intended for patients with metastatic ALK-positive NSCLC who were previously treated with crizotinib, the only other approved ALK tyrosine kinase inhibitor. Zykadia was the fourth drug  to receive breakthrough therapy designation from the FDA. The Food and Drug Administration Safety and Innovation Act, passed in July 2012, gave the FDA the ability to designate a drug a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates that the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. A breakthrough therapy designation conveys all of the fast track program features as well as more intensive FDA guidance on an efficient drug-development program.

Gilead Sciences also received approval for Zydelig (idelalisib), which is indicated to treat three types of blood cancer, making it the second NME with breakthrough status to be approved in 2014 after Novartis’ Zykadia and the fifth NME with breakthrough status to be approved since the program was started in 2012. Zydelig was approved to treat patients whose chronic lymphocytic leukemia (CLL) has returned (relapsed) as well to two treat two other indications: relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma, another type of non-Hodgkin lymphoma. The FDA approved Roche’s Gazyva (obinutuzumab) in November 2013, a new indication for Janssen Biotech/Pharmacyclics’ Imbruvica (ibrutinib) in February 2014, and a new use for GlaxoSmithKline’s Arzerra (ofatumumab) in April 2014 to treat CLL. Both Gazyva and Arzerra also received breakthrough therapy designation for this indication.

Takeda Pharmaceutical received approval for its NME, Entyvio (vedolizumab) injection, for treating adult patients with moderate-to- severe ulcerative colitis (UC) and adult patients with moderate-to-severe Crohn‘s disease (CD). Entyvio is an integrin receptor antagonist. Integrin receptors are proteins expressed on the surface of certain cells. Integrin receptors function as bridges for cell-cell interactions. Entyvio blocks the interaction of a specific integrin receptor (expressed on circulating inflammatory cells) with a specific protein (expressed on cells in the interior wall of blood vessels), and thereby blocks the migration of those circulating inflammatory cells across those blood vessels and into areas of inflammation in the gastrointestinal tract. In March 2014, Entyvio received a positive opinion for the treatment of adults with moderately to severely active UC and CD from the Committee for Medicinal Products for Human Use  of the European Medicines Agency (EMA),and Takeda is awaiting response from the European Commission on approval for marketing authorization.

Biogen Idec received FDA approval for Plegridy (peginterferon beta-1a) as a treatment for adults with relapsing-remitting multiple sclerosis, the most common form of multiple sclerosis. Plegridy is dosed once every two weeks and is administered subcutaneously with the Plegridy Pen, a new ready-to-use autoinjector, or a prefilled syringe. Plegridy is interferon beta-1a that has been pegylated to extend its half-life to permit a less frequent dosing schedule. In July, the European Commission granted marketing authorization for the drug as well.

Sanofi received FDA approval for its NME, Cerdelga (eliglustat), a first-line oral therapy for the long-term treatment of certain adult patients with the Type 1 form of Gaucher disease, a rare genetic disorder. The drug also received orphan drug status from the FDA. The new oral drug was developed by Sanofi’s Genzyme subsidiary, which also developed Cerezyme (imiglucerase for injection), which is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease. Cerezyme posted 2013 sales of EUR 688 million ($913 million) and is one of several enzyme-replacement therapies by Sanofi to treat rare diseases. Others are: Myozyme/Lumizyme (alglucosidase alfa) to treat Pompe disease; Fabrazyme (agalsidase beta) to treat Fabry disease; and Aldurazyme (laronidase) to treat mucopolysaccharidosis Type I. Marketing applications for Cerdelga are under review by the EMA and other regulatory authorities.

Other companies received approvals of orphan drugs. Janssen Biotech received FDA approval for an orphan drug, Sylvant (siltuximab), to treat patients with multicentric Castleman’s disease. Chelsea Therapeutics, which was acquired by H. Lundbeck A/S (Lundbeck) for $658 million in June 2014, received approval for its orphan drug, Northera (droxidopa), for the treatment of neurogenic orthostatic hypotension (NOH). NOH is a rare, chronic drop in blood pressure upon standing that is associated with Parkinson’s disease, multiple-system atrophy, and pure autonomic failure, dopamine beta hydroxylase deficiency, and non-diabetic autonomic neuropathy.

Table I: Approvals of New Molecular Entities (New Drug Applications (NDAs) and Original Biologics License Applications (BLAs)) by FDA’s Center for Drug Evaluation and Research in 2014 (as of August 25, 2014)
Company Proprietary Name (Active Ingredient) Dosage Form/Route of Administration Indication
Anacor Pharmaceuticals Kerydin (tavaborole); NDA       Solution/topical Topical treatment of onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes
AstraZeneca Farxiga (dapaglifozin); NDA  Tablet/oral To improve glycemic control, along with diet and exercise, in adults with Type 2 diabetes
AstraZeneca Myalept (metreleptin); BLA Injectable/injection To treat metabolic disorders secondary to lipodystrophy
Biogen Idec Plegridy (peginterferon beta-1a); BLA       Injectable/injection To treat relapsing forms of multiple sclerosis
BioMarin Pharmaceutical Vimizim (elosulfase alfa); BLA Injectable/injection To treat Mucopolysaccharidosis Type IVA (Morquio A syndrome)
Boehringer Ingelheim Pharmaceuticals Jardiance (empagliflozin); NDA        Tablet/oral To improve glycemic control in adults with Type 2 diabetes
Boehringer Ingelheim Pharmaceuticals Striverdi Respimat (olodaterol); NDA    Spray, metered; inhalation Long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease, including chronic bronchitis and/or emphysema
Celgene Otezla (apremilast); NDA        Tablet/oral To treat adults with active psoriatic arthritis
Chelsea Therapeutics Northera (droxidupa); NDA       Capsule/oral To treat neurogenic orthostatic hypotension
Cubist Pharmaceuticals Sivextro (tedizolid phosphate); NDA        Tablet/oral and Powder/ IV Infusion Acute bacterial skin and skin structure infections
Durata Therapeutics Dalvance (dalbavancin); NDA       Injectable; IV (infusion) Acute bacterial skin and skin structure infections
Eli Lilly Cyramza (ramucirumab); BLA Injectable/injection To treat advanced stomach cancer or gastroesophageal junction adenocarcinoma
Gilead Sciences Zydelig (idelalisib); NDA        Tablet/oral To treat three types of blood cancer
GlaxoSmithKline Tanzeum (albiglutide); BLA Injectable/injection To improve glycemic control, along with diet and exercise, in adults with Type 2 diabetes.
Janssen Biotech Sylvant (siltuximab); BLA Injectable/injection To treat patients with multicentric Castleman’s disease
Merck & Co. Belsomra (suvorexant); NDA       Tablet/oral To treat difficulty in falling and staying asleep (insomnia)      
Merck & Co. Zontivity (vorapaxar); NDA        Tablet/oral To reduce the risk of heart attack, stroke, cardiovascular death, and need for procedures to restore blood flow to the heart in patients with a previous heart attack or blockages in the arteries to the legs
Novartis Zykadia (ceritinib); NDA       Capsule/oral To treat patients with a certain type of metastatic non-small cell lung cancer
Paladin Therapeutics Impavido (miltefosine); NDA       Capsule/oral To treat the tropical disease leishmaniasis
Piramal Imaging Neuraceq (florbetaben F 18 injection); NDA        Solution/intravenous For positron emission tomography imaging of the brain
Sanofi Cerdelga (eliglustat); NDA        Capsule/oral Long-term treatment of adult patients with Type 1 Gaucher disease
Spectrum Pharmaceutical Beleodaq (belinostat); NDA        Powder; IV Infusion Peripheral T-cell lymphoma
Takeda Pharmaceutical Entyvio (vedolizumab); BLA Injectable/injection Moderate-to-severe ulcerative colitis and severe Crohn‘s disease in adults
The Medicines Company Orbactiv (oritavancin); NDA       Powder for injection, solution/lyophilized powder Acute bacterial skin and skin structure infections
Valeant Pharmaceuticals Jublia (efinaconazole); NDA       Solution/topical Topical treatment of onychomycosis of the toenails due to Trichophyton rubrum and Trichophyton mentagrophytes
Vanda Pharmaceuticals Hetlioz (tasimelteon); NDA       Capsule/oral To treat non-24-hour sleepwake disorder in blind individuals without light perception

AstraZeneca completed the acquisition of its diabetes alliance from Bristol-Myers, which include Myalept, in February 2014. As part of the sale of its diabetes alliance (excluding China) to AstraZeneca, Bristol-Myers Squibb received from AstraZeneca a payment of approximately $2.7 billion at closing and a subsequent milestone payment of $600 million for the US approval of Farxiga (dapagliflozin). The company also received $100 million for the approval of dapagliflozin in Japan. Bristol-Myers Squibb will potentially receive additional regulatory- and sales-based milestone payments from AstraZeneca of up to $700 million, royalty payments based on net sales through 2025, and additional payments if and when certain assets are subsequently transferred.

Boehringer Ingelheim and Eli Lilly partnered for Jardiance as part of the companies’ diabetes alliance.

Chelsea Therapeutics was acquired by H. Lundbeck A/S in June 2014.  

Valeant Pharmaceuticals acquired Jublia (efinaconazole) from its 2008 acquisition of Dow Pharmaceutical Science.

Source: US Food and Drug Administration.  

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