New Drug Approvals in 2013: What Was Hot, What Was Not

The FDA approved 27 new molecular entities in 2013. As the year draws to a close here's an opportunity to look back at the predicted blockbusters - and those that just plain busted, too - as they passed through the FDA agency halls. From Tecfidera for MS, Sovaldi for HCV, and continuing the year-end push with Anoro Ellipta for COPD, take a look at the winning approvals, and those that may need a revisit to the FDA in 2014.

Dimethyl fumarate (Tecfidera) by Biogen Idec

Tecfidera was FDA-approved in March 2013. Tecfidera, also known as BG-12, is an oral Nrf2 pathway activator for the treatment of relapsing-remitting multiple sclerosis. Biogen Idec's immune modulator produced few side effects in clinical trials and met efficacy outcomes.

Analysts say the highly anticipated Tecfidera could have sales of up to $6 billion annually by 2020. A year's supply of Tecfidera will run close to $55,000. Other oral competitors include Aubagio and Gilenya.

Canagliflozin by Janssen Pharmaceuticals

Canagliflozin (Invokana) is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor approved in April 2013 for the treatment of type 2 diabetes. Canagliflozin improves sugar control, weight loss and blood pressure.

The FDA Advisory Committee expressed concern over cardiovascular safety, but the FDA followed-up by ordering five post-marketing safety trials looking at cardiovascular safety to cancer risk. Nonetheless, some analysts predict this drug to be a blockbuster by 2018.

Elvitegravir by Gilead

Elvitegravir is an integrase inhibitor used for the treatment of HIV-1 infection in patients who have previously received HIV treatment. Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir), Gilead’s once-daily HIV-1 treatment, was approved in August 2012.

Gilead is also seeking approval of the pharmacokinetic enhancer cobicistat as a single entity agent. On April 29, 2013 Gilead received the Complete Response Letters from the FDA for both elvitegravir and cobicistat; deficiencies were found in the NDA. Approval is pending.

Cobicistat by Gilead

Cobicistat, Gilead's pharmacokinetic enhancer is already approved as a drug contained in Stribild, a combination HIV treatment. Cobicistat is used to boost blood levels of other HIV medications to make them more effective and is meant to be used in combination.

Cobicistat inhibits CYP3A4, an enzyme responsible for breaking down some HIV drugs, but it is not active against HIV itself. The NDA was submitted in June 2012, but initial approval was rejected in 2013 due to deficiencies in documentation and validation of certain quality testing procedures and methods. The FDA did not raise safety concerns about the drug.

Buprenorphine (Probuphine) by Titan Pharmaceuticals

Probuphine is a long-acting, subdermal implant that delivers six months of slow-release buprenorphine. The NDA was submitted to the FDA for the maintenance treatment of opioid dependence in adult patients.

Buprenorphine, already approved and well-accepted for the treatment of opioid dependence surpassed 2011 U.S. sales of $1.3 billion. On April 30, 2013, the FDA issued a complete response letter stating they could not approve the application in its present form; they required additional data supporting the efficacy of Probuphine.

Fluticasone furoate/vilanterol (Breo Ellipta) by GSK & Theravance

Breo Ellipta (fluticasone furoate/vilanterol) is a once daily, inhaled corticosteroid plus long-acting beta2 agonist (LABA). Breo Ellipta was approved in May 2013 for patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Breo Ellipta decreases inflammation and relaxes airway muscles to improve breathing.

COPD is a chronic lung disease that worsens over time. Cigarette smoking is the leading cause of COPD and is the third leading cause of death in the United States.

Gabapentin Extended Release (Sefelsa) by DepoMed

Sefelsa is the proposed name for Depomed's extended-release formulation of gabapentin for the treatment of hot flashes. Gapapentin is approved to treat pain and seizures, and doctors also prescribe the drug off-label (without an FDA approval) for menopause symptoms.

However, at the FDA Advisory Committee meeting in March 2013 the committee voted 2-12 against approval for Sefelsa. A complete response letter was received at the end of May and Depomed has halted production of Sefelsa.

Dabrafenib (Tafinalar) by GlaxoSmithkline

GSK is hoping to bolster oncology product lines with the FDA approval of oral dabrafenib for the treatment of patients with advanced melanoma with BRAF V600E mutations. Malignant melanoma is a cancerous tumor of skin cells that produce pigment (melanin).

Dabrafenib, a BRAF inhibitor, blocks kinase to inhibit cancer cell growth. Vemurafenib (Zelboraf) by Genentech is currently approved for a similar use. In May 2013, Tafinalar was approved along with a diagnostic genetic test to identify patients for treatment.

Trametinib (Mekinist) by GlaxoSmithkline

In addition to dabrafenib, GSK has developed oral trametinib (Mekinist), the first mitogen-activated, extracellular signal–regulated kinase (MEK) inhibitor, also for treatment of advanced melanoma. In May, 2013 Mekinist was FDA-approved for patients whose tumors express the BRAF V600E or V600K gene mutations with a diagnostic test.

In addition, GSK has ongoing clinical trials looking at the use of dabrafenib and trametinib in combination to delay or prevent cancer recurrence in this high-risk group after melanoma surgical removal.

Tivozanib by AVEO and Astellas

Aveo and Astellas submitted tivozanib for the treatment of advanced renal cell carcinoma (kidney cancer). Tivozanib targets the vascular endothelial growth factor (VEGF) pathway.

In May, 2013, an FDA Advisory Committee voted 13 to 1 against approval of tivozanib, stating the NDA for tivozanib did not demonstrate a favorable benefit-to-risk ratio for treatment of metastatic renal cell carcinoma. In June 2013 the FDA rejected AVEO Oncology's NDA for tivozanib due to an imbalance in progression-free and overall survival results.

Levomilnacipran ER (Fetzima) by Forest Labs

Levomilnacipran (Fetzima) is an oral serotonin-norepinephrine reuptake inhibitor (SNRI) developed for the treatment of major depressive disorder (MDD) in adults. Levomilnacipran is an enantiomer of racemic milnacipran (brand name Savella) which is indicated for treatment of fibromyalgia in the U.S., but not depression.

On July 25, 2013 the FDA approved levomilnacipran for MDD. It will be available as a once-daily, extended-release capsule in 40, 80 or 120 mg strengths. Forest Labs expects Fetzima to be launched to retail stores in 4th quarter 2013.

Dolutegravir by ViiV Healthcare

The FDA granted a priority review to dolutegravir, a once-daily oral integrase inhibitor for the treatment of HIV infection, meaning the drug has potential to offer significant improvement over existing therapies. Integrase inhibitors work by blocking HIV replication. Phase 3 clinical trials evaluated 2553 patients with HIV/AIDS ranging from therapy naïve to salvage patients. On August 12, 2013 the FDA approved Dolutegravir (Vivicay), to be used in combination with other HIV treatments.

Dolutegravir is expected to be a major competitor for Gilead's HIV treatment Atripla and Merck's Isentress.

Bazedoxifene/Conjugated Estrogens (Duavee) by Pfizer & Ligand Pharma

Duavee (bazedoxifene/conjugated estrogens) is a tissue selective estrogen complex. Duavee is approved for use in non-hysterectomized women for the treatment of moderate-to-severe vasomotor symptoms (hot flashes), as well as the prevention of postmenopausal osteoporosis. Duavee was approved by the FDA in October 2013.

Duavee pairs a selective estrogen receptor modulator bazedoxifene with estrogen, and is the first TSEC. Brisdelle (paroxetine), also approved by the FDA in 2013, is the first non-hormonal treatment for hot flashes associated with menopause.

Methotrexate Injection (Otrexup) by Antares Pharma

Otrexup (methotrexate) is a new technology for the subcutaneous self-injection of methotrexate (MTX), the gold standard in rheumatoid arthritis (RA) therapy. Otrexup has been approved for treatment of RA, juvenile RA, and psoriasis. Otrexup is delivered via the proprietary Medi-Jet technology. According to the manufacturer, Otrexup use could result in lower RA healthcare costs by delaying the use of costly biologic agents and expanding the use of an easier-to-use injectable MTX. Clinical trials have shown that the self injection device is easy to use, even for patients with RA in their hands. Commercial availability is expected in early 2014.

Macitentan (Opsumit) by Actelion

Opsumit (macitentan) was FDA-approved in October 2013. Opsumit is an oral, dual endothelin receptor antagonist for the treatment of patients with pulmonary arterial hypertension (PAH). PAH is a life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs. Placebo-controlled trials spanned two years with over 740 patients. Opsumit was found to be effective in delaying disease progression including a decline in the ability to exercise, worsened PAH symptoms or added medication. Opsumit is in a restricted access program due to a class risk for birth defects. Opsumit is similar to the PAH drugs Tracleer (bosentan) and Letairis (ambrisentan).

Umeclidinium bromide/vilanterol (Anoro) by GlaxoSmithkline/Theravance

Anoro Ellipta combines two inhaled chronic obstructive pulmonary disease (COPD) bronchodilator agents, umeclidinium bromide (UMEC), a long-acting muscarinic antagonist and vilanterol (VI), a long-acting beta2 agonist. VI is also found in a once-a-day COPD combination with fluticasone furoate (Breo) - approved in May 2013. GSK is developing a new line of respiratory agents to replace the cornerstone blockbuster Advair Diskus. In September 2013, the FDA Advisory Committee recommended approval with post-market safety studies suggested due to cardiovascular concerns. FDA made final approval of Anoro Ellipta on December 18, 2013.

Sofosbuvir by Gilead

Sofosbuvir, a once-daily nucleotide analog inhibitor, is under study for the $5 billion-plus hepatitis C virus (HCV) market. Sofosbuvir inhibits RNA polymerase and blocks viral replication. Interest lies in using Gilead's sofosbuvir in interferon-free, all-oral regimens for HCV treatment. In clinical trials sofosbuvir has fared well. According to analysts, annual sales could reach $4 billion by 2016. NDA filing was completed in April 2013 and the FDA granted sofosbuvir a priority review in June. An FDA Advisory panel unanimously recommended approval of sofosbuvir in October 2013, and the FDA is expected to make a final decision by December 8, 2013.

Suvorexant by Merck

Suvorexant is Merck's investigational controlled drug for insomnia. Suvorexant blocks orexin - a brain chemical that keeps people awake - and would be the first in a new class called orexin receptor antagonists. Suvorexant may also be helpful for night shift workers who need daytime sleep.

In July, the FDA rejected Merck's NDA, saying a lower 10-mg start dose should be developed; the 15 and 20 mg doses would be appropriate if the 10 mg dose is well-tolerated but not effective. Approval could be delayed by up to one year. Analysts predict sales peak may range from $700 million to $1.5 billion for suvorexant by 2018.

Sources

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