New Drugs, First Generics, and the Near-Term Pipeline 2012

In the wake of what was the Food and Drug Administration’s (FDA’s) lowest new drug approval total in several years, the pharmaceutical industry is once again showing signs of life. The FDA’s Center for Drug Evaluation and Research approved a total of 21 new drugs in 2010; of these, 15 were new molecular entities (NMEs) and 6 were novel therapeutic Biologic License Applications (BLAs). As of July 20, 2011, the agency has approved 19 new drugs: 16 NMEs and 3 BLAs. Furthermore, of the 19 new drugs approved by the FDA this year, several have blockbuster sales potential, defined as a product that generates at least $1 billion in annual revenue for the manufacturer that produces it. These include new treatments for hepatitis C, lupus, and melanoma.

The new approvals of potential blockbusters represent a significant new source of revenue for pharmaceutical manufacturers, who will also experience a significant loss of income from blockbuster products expected to see generic competition for the fi rst time in 2011. The year has thus far seen the introduction of generic versions of Concerta and Levaquin. Before the year is out, generic versions of Lipitor and Zyprexa are expected.^1-3

NEW DRUG APPROVALS 2011

New drug approvals are but 1 element—albeit a significant one—among many factors that impact drug spending via increased utilization. Other factors include new approved indications, reformulations, off-label drug use, changing demographics (eg, our aging population), pharmacy benefit designs, pharmaceutical promotional spending, new treatment guidelines, and the economy.

A full list of new drug approvals through July 20, 2011, can be found in the Table, including all NMEs and therapeutic BLAs approved by the Center for Drug Evaluation and Research. The most significant of these identified as having a strong potential impact on utilization, cost, and overall trend include the following:

Human Genome Sciences’ biologic Benlysta (belimumab), approved in March, is the fi rst new drug for lupus in more than 50 years.⁴ The company said Benlysta would cost (at launch) $443 for a 120-mg vial and $1477 for a 400-mg vial. The FDA puts the systemic lupus population at around 300,000 minimum.⁵

Another biologic, Bristol-Myers Squibb’s injectable drug Yervoy (ipilimumab), was approved in March for late-stage or metastatic melanoma, and is the first drug shown to prolong the lives of patients with this form of advanced skin cancer. It will be priced at $30,000 per injection, for a total price of $120,000. Melanoma is the deadliest type of skin cancer, but the FDA has only approved 2 other drugs for advanced melanoma. The newer of those drugs was cleared more than 13 years ago. Neither drug has been shown to significantly extend patient lives.⁶

The FDA approved 2 new hepatitis C treatments in May: Merck’s Victrelis (boceprevir) and Vertex Pharmaceuticals’ Incivek (teleprevir). Merck said the wholesale acquisition cost (WAC) for Victrelis will be $1100 per week,⁷ dosed for 24 to 44 weeks, whereas Vertex said Incivek would carry a price of $49,200 for a 12-week course of therapy. The WAC for Incivek will be only $800 higher for the course of therapy than the WAC for Victrelis when patients take that drug for 44 weeks. But for Victrelis patients who receive the drug for 24 weeks, the cost will be significantly lower than that for Incivek. The duration of treatment with Victrelis, however, is not determined until after starting treatment. Both agents produced a substantially greater sustained virological response rate compared with the existing standard of care.⁸

On July 1, the FDA approved Johnson & Johnson/Bayer’s Xarelto (rivaroxaban) to prevent certain blood clots, known as venous thromboembolisms, in people undergoing knee- and hip-replacement surgery. Johnson & Johnson said Xarelto is the first new oral anticoagulant approved to prevent venous thromboembolisms in joint-replacement surgeries. An older drug used for this purpose, Lovenox (enoxaparin), is injected. A bigger market for Xarelto lies in its use to prevent strokes in people with atrial fibrillation. The companies have filed for approval to market Xarelto for this use, and a decision could come later this year from the FDA. Xarelto was launched shortly after approval with a WAC of $6.75 per unit.⁹

Also in July, the FDA approved AstraZeneca’s Brilinta (ticagrelor) to reduce thrombotic events in patients with acute coronary syndrome, including unstable angina, and in patients with myocardial infarction who are candidates for stenting. Acute coronary syndrome includes a group of symptoms for any condition, such as unstable angina or heart attack, that could result from reduced blood flow to the heart. The FDA said Brilinta’s label will include a “boxed warning to healthcare professionals and patients warning that aspirin doses above 100 mg per day decrease the effectiveness of the medication.” A widely touted benefit of Brilinta is that its effect can be quickly switched off because it has a much shorter half life than either of the 2 approved antiplatelets, Plavix (clopidogrel) and Effient (prasugrel). A limitation of Brilinta’s pivotal trial program is that most of the patients came from Europe, the Middle East, or Africa. Only 11% of the patients were recruited in North America. In that cohort, Brilinta-treated patients were 27% more likely to suffer one of the end point events, although the difference fell short of statistical significance.

As new drugs become available, prescribing guidelines are updated and may impact utilization trends. An example of this is the updated protocol for treatment of atrial fibrillation published by the American College of Cardiology (ACC) and the American Heart Association (AHA). Pradaxa (dabigatran) capsules were approved by the FDA in October 2010 for prevention of stroke and systemic embolism in patients with atrial fibrillation, making it the first oral anticoagulant to enter the market since warfarin (Coumadin and generics) was approved in the 1950s. While Pradaxa is exponentially more expensive than generic warfarin, its competitive advantage and market positioning relate to superior efficacy; in a pivotal study used to support approval, Pradaxa patients had 34% fewer strokes and systemic embolisms than warfarin patients.¹⁰ While the approval of Pradaxa in October came too late for inclusion in the new ACC/AHA guidelines published in December,¹¹ an additional update was published by the groups in February 2011 that said that Pradaxa can be used as an alternative to warfarin to prevent blood clots and stroke in certain atrial fibrillation patients.¹²

Arguably, the most significant approvals for the year have already been made, based on the list of products that have a 2011 review goal date at the FDA. However, a number of other novel products are expected to receive a review at the agency before the end of the year, including:

Firazyr (icatibant), Shire’s hereditary angioedema (HAE) drug, won support from an FDA advisory committee for a claim to allow patients to self-inject the product, which would distinguish it from established treatments that must be delivered by a physician or infused in a clinical setting. Additionally, because HAE attacks are unpredictable, the ability to self-inject and receive the medication quickly is very important to patients. The HAE treatment population is small (an estimated 7000 Americans suffer from HAE), so Firazyr is likely to be costly if approved.^13,14 (NOTE: Firazyr was approved by the FDA on August 25, 2011.)

Ruxolitinib, Incyte’s myelofibrosis (a disorder of the bone marrow) candidate, demonstrated superiority compared with the best available therapy with respect to reducing splenomegaly and alleviating symptoms in patients with myelofibrosis. Also, ruxolitinib treated patients saw a reduction in a variety of disease-related symptoms; patients receiving the existing standard of care did not.¹⁵

OUTLOOK FOR 2012

Significant new drug approvals that could occur in 2012 include the following:

Apixaban, by Bristol-Myers Squibb/Pfizer, is from the same class of blood thinners as Xarelto. Although it will be the third new oral anticoagulant to reach the market (following Pradaxa and Xarelto), in certain clinical settings it has demonstrated superiority to warfarin on safety and efficacy, which could help it gain market share against established products. Xarelto was shown to be noninferior, not superior, to warfarin on efficacy and bleeding in a pivotal study. Pradaxa demonstrated superior efficacy compared with warfarin, but it had a comparable risk of bleeding. The projected 2012 market entry is based on the intent by Bristol-Myers Squibb/Pfizer to file for FDA approval in the third or fourth quarter,¹⁶ and assumes a standard review.

Bydureon (exenatide) is Eli Lilly/Alkermes’ once-weekly subcutaneous injectable glucagon-like peptide-1 analog for type 2 diabetes. The companies recently said that they plan to resubmit Bydureon to the FDA in the third or fourth quarter after announcing that the drug met the primary end point of an FDA-mandated cardiovascular risk study. In a 3-year study, patients treated with Bydureon showed sustained decreases in blood sugar, weight loss, and improvements in blood pressure and cholesterol levels.¹⁷

In 2012, the number and significance of the brand-name drugs losing marketing exclusivity via the so-called “patent cliff” will experience a maximum value in terms of sales dollars at risk, with first-generic entries projected for Actos, Diovan, Geodon, Lexapro, Plavix, Provigil, Seroquel, and Tricor. Before the year is out, generic versions of Lipitor and Zyprexa are expected.^1-3 Approximately $25 billion in domestic brand sales are expected to be lost to generic drugs in 2011, according to IMS Health, which noted that the amount of brand sales lost to generic drugs in 2010, by comparison, was half that amount. The company has characterized the first-generic approvals in 2011 and 2012 as the largest generic opportunities ever, in terms of the protected brand sales that will be exposed to generic competition.18