From Promise to Payoff - Pharmaceutical Executive


From Promise to Payoff

Pharmaceutical Executive


So many targets, so little time

Denosumab (Prolia), Amgen's anti-osteoporosis monoclonal antibody, is also in late-stage tests for the treatment of bone metastases related to cancer. The drug targets RANK Ligand, one of the proteins active in osteoclasts, which destroy bone cells. Metastatic activity can result in so-called skeletal-related events (SREs), including bone fracture, radiation to bone, surgery to bone, or spinal cord compression. In a 2,000 patient Phase III trial, denosumab proved superior to Novartis's zoledronic acid (Zometa) in preventing SREs and delaying increases in bone pain.

Amgen needs a blockbuster badly. Yet denosumab faced a setback in October when FDA delayed approval for indications for bone loss in breast and pancreatic cancers; the bone-metastasis indication has yet to come out of the advisory board. Tolerability may be the biggest selling point for the new drug. Says Fleur Pijpers, an analyst with Datamonitor: "When patients receive Zometa, they have to have their kidney function monitored quite regularly. Denosumab doesn't need that. And it's got a more convenient administration by subcutaneous injection.

Sales for denosumab in all uses, including osteoporosis, could reach $5 billion in 2015, Geoffrey Porges of Sanford Bernstein told the Wall Street Journal. Other analysts project sales of 30 percent less. Projections vary in part because Amgen has not said how it will price the drug, although an annual price tag of $1,500 to $2,000 is expected.

Ipilimumab, a novel monoclonal antibody that blocks the effects of the negative T cell regulator CTLA-4, targets malignant melanoma, prostate cancer, lymphoma, and lung cancer by strengthening the immune response to tumor cells. "Bristol liked this drug so much that they bought the company," says Les Funtleyter of Miller Tabak. BMS paid $2.1 million for Medarex, a boutique specializing in monoclonal antibodies— a hefty pricegiven that Ipilimumab's peak sales aren't due to exceed $400 million. Another Medarex anti-CTLA-4, tremelimumab, was discontinued by Pfizer in Phase III against malignant melanoma after the drug failed to show superiority against available chemo. It is still being tested in phase II prostate and bladder cancers, among others.

Lilly's Enzastaurin is the most advanced of the PI3K inhibitors, a relatively new class of drugs that exploit a pathway in the familiar antiangiogenic approach to tumor control. "Everybody has a PI3K drug—it's a big pathway," Funtleyter says. By interfering with PI3K in the protein kinase B signaling pathway, enzastaurin increases the permeability of the mitochondrial membrane, which can result in apoptotic cell death. Lilly got the jump on the competition, few of which have adanced beyond Phase I. Enzastaurin is in Phase III trials for non-Hodgkin's lymphoma and in eight Phase II trials for other types of tumors.

Abiraterone is a potential second line therapy for prostate cancer. The drug showed good results in Phase II studies on tumors in patients who had not received chemotherapy, and also in patients resistant to hormone therapies that caused the testicles to stop producing testosterone. Experts believe that these tumors continue to grow because they can feed on testosterone produced elsewhere in the body or by the tumor itself. "What is most striking is that it seems to have an anti-tumor effect in refractory or resistant patients," Pijpers says, noting that it starves tumors because it inhibits an enzyme necessary to the production of testosterone anywhere in the body.

Abiraterone was discovered by the Institute of Cancer Research in London and licensed to Cougar Biotechnology. Johnson & Johnson acquired the drug by purchasing the cancer biotech for $870 million in July. Datamonitor estimates abiraterone's peak sales to reach almost $900 million for all potential indications, while Decision Resources projects prostate cancer sales to reach over $500 million in 2018.

Another new class of cancer drugs is known as PARP inhibitors. The PARP, or Poly (ADPribose) polymerase, enzyme regulates gene transcription and repair, especially in cancer cells, so blocking it slows cell growth. At the recent meeting of the American Society of Clinical Oncology, the two leading PARP inhibitors—BSI-201 from BiPar and Sanofi-Aventis and olaparib from KuDOS and AstraZeneca—released eye-catching Phase II data. "It's quite rare for drugs to create such a buzz just based on the Phase II data. So these certainly make you sit up and notice," says Pijpers.

In BSI-201's Phase II trial, researchers treated triple-negative breast cancer. One in seven breast cancer patients falls into this highly unmet need group. As HER2 negative patients, they cannot be treated with a variety of hormone therapies, even though they have a hormone-driven disease. "In this trial," Pijpers says, "BSI-201 was combined with Gemzar and carboplatin. Researchers reported an improvement in progression-free survival of 6.9 months compared to 3.3 months in the chemotherapy arm."

Provenge, Dendreon's prostate cancer vaccine, first attracted attention in this report at least five years ago. At the time, experts were predicting a 2007 launch, but now the drug may finally be ready for its FDA close-up. The first-in-class vax fuses cellular components from the patient's own immune system onto the sort of dendritic cell that typically presents an antigen. The vaccine is acting as a guided missile that shoots down prostate cancer cells. The dendritic cell carries prostate-specific antigen PSA, an enzyme that occurs with prostate cancer, and an agent that stimulates the growth of white blood cell colonies that fight the disease.

"It's a personalized cancer therapy—a completely new idea of using a patient's immune system to fight cancer," says Tom Gray, an analyst at Datamonitor. "And it would be the first therapeutic cancer vaccine to reach the market." Data released in April showed that the vaccine increased the length of median overall survival of mildly symptomatic metastatic resistant prostate cancer patients to 25.8 months compared to 21.7 months for placebo.

Two big questions that may cause Provenge to disappoint: Is FDA, which has says it will decide the vaccine's fate by May 1, privy to any negative data that has gone unpublished? And just how much personalization is a good thing? "It may be really increasing the level of inconvenience for the patient," Gray says, "Where you have an off-the-shelf drug like Taxotere that you can give to the patient then and there as opposed to having to waitmaybe a week to administer the vaccine." Datamonitor estimates Provenge's peak sales at $300 million plus change, while Decision Resources sees blockbuster status—$1.1 billion in 2018.


A surge of new combination therapies of new (and not-so-new) drugs

The chronic obstructive pulmonary disease (COPD) market is on track to nearly double by the end of the coming decade. In 2008, COPD was a $7 billion market worldwide. By 2018, the market will reach $11.5 billion, according to Amy Whiting, an analyst at Decision Resources. At the same time, none of the drugs currently on the market—and, more surprisingly, none set to launch by 2018—are disease-modifying or improve lung function over the long term, Whiting says.

Innovation remains incremental in this space. And since bronchodilators are almost always combination therapies, the trend among drugmakers is to combine a newly formulated compound to with one the firm is already marketing. The benefits for patients are convenience in dosing. The challenge for pharmas will be to differentiate these combinations in the marketplace.

Indacaterol, a long-acting beta-2 agonist (LABA), promises a 24-hour effect as a bronchodilator—about twice as long as most current LABAs. It's a component of two new experimental compounds, both from Novartis. Combined with the anti-inflammatory mometasone, an inhaled corticosteroid (ICS), the drug is known as QMF 149. In combination with the bronchodilator glycopyrrolate, a long-acting muscarinic antagonist (LAMA), the drug is called QVA 149. Both drug combinations are completing Phase II trials. Analysts, including Whiting, see these fast-acting, once-daily treatments as blockbusters in the growing market.

The Novartis LABA/LAMA combo faces competition from Forest's Aclidinium, a new LAMA being tested in combination with the widely marketed LABA formoterol. The most promising new LABA/LAMA combination, according to Whiting, pairs the Boehringer Ingelheim LABA component, BI-1744-CL, with the LAMA tiotropium, marketed in the US as Spiriva. "As far as combined US and European sales, we expect that to be over $1.2 billion in 2018," Whiting says.

Competing with Novartis's QMF 149, GlaxoSmithKline and Theravance are running Phase III tests of GW 642444, a new LABA, with fluticasone furoate, an ICS. "That would be the most promising, as far as the emerging LABA/ICSs," Whiting says. She projects peak sales of $815 million in 2018.

Many of these drugs may be available as monotherapies, but the combinations are the future of this sector. Says Whiting: "We expect three new LABA/LAMA combinations to garner nearly 20 percent of the 2018 COPD markets. So they are going to take share away from some of the currently available LABAs and LAMAs that may be prescribed individually."

In addition to bronchodilators like the LABAs and LAMAs, COPD can be treated with anti-inflammatories, including the class of phosphodiesterase 4 inhibitors, such as roflumilast, an oral once-daily from Forest and Nycomed. The firms have already filed an NDA under the name Daxas in Europe and in the US. Whiting expects the drug to launch in Europe but says she is "hesitant about its place in the United States" because FDA will look askance at the gastrointestinal side effects and weight loss that have plagued patients in clinical trials. The cautious physician may use it as an add-on to bronchodilator therapy.


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