Replies to post #80585 on Biotech Values

[DewDiligence]

AMGN re: Good News, Bad News on Denosumab

There was no statistically significant difference in the rate of ONJ between the two treatment arms.

This wording strongly suggests that the observed ONJ rate was somewhat higher in the D-mab arm than in the Zometa arm. However, this is a relatively minor negative in the overall scheme of things—much less consequential than the fact that D-mab showed superiority on Zometa on the primary endpoint.

In AH trading, AMGN was up 13% and NVS was down 3%. The NVS drop is an overreaction, IMO.

[genisi]

Amgen's Uphill Marketing Battle

http://www.businessweek.com/technology/content/jul2009/tc2009078_741612.htm

Shares of the biotech giant surged on signs its bone-loss treatment is effective, but getting doctors to prescribe the drug will be tough

By Arlene Weintraub

When biotechnology giant Amgen (AMGN) announced study results for its experimental bone-loss treatment denosumab, Wall Street cheered.

In a head-to-head trial against the popular Novartis (NOVN) drug Zometa, denosumab was clearly superior in treating breast cancer patients who suffered bone loss when their cancer spread, according to research results released July 7. Deutsche Bank (DB) added $550 million to its forecast of the drug's peak annual sales, suggesting it could someday bring in $3 billion a year. Other analysts were even more bullish, predicting the drug could generate $1 billion to $2 billion in the breast-cancer market alone—that's on top of what Amgen might haul in by selling the drug to women with post-menopausal osteoporosis. Early in the day's trading session, Amgen's stock soared 15%, to 60 a share, before closing at 59.50.

The rally was fueled by some mighty big expectations that won't be easy for Thousand Oaks (Calif.)-based Amgen to meet. For starters, the Food & Drug Administration won't decide whether to approve the drug until October. More important, in getting doctors to prescribe the drug and patients to clamor for it, Amgen may be facing its biggest marketing challenge yet. The osteoporosis market is dominated by some of the most famous names in pharmaceuticals: Roche's Boniva, Novartis' once-yearly version of Zometa called Reclast, and Merck's (MRK) Fosamax, which went generic last year. About 38 million prescriptions are written for bone-loss treatments every year, and the market reached $4.6 billion in sales in 2007, according to IMS Health (RX). Total sales dropped 22% last year when cheap versions of Fosamax became available.

Breaking Down Barriers

Denosumab will offer some distinct advantages over its rivals. In post-menopausal osteoporosis, patients will be able to get denosumab as a twice-yearly injection from primary-care doctors. That will make it more convenient than Fosamax, which is a daily or weekly pill, and Boniva, which patients take monthly. And unlike some of the older drugs, denosumab does not seem to touch off a frightening side effect called osteonecrosis of the jaw (ONJ), which can cause pain and bone protrusions in the mouth. (In the most recent trial, ONJ was rare in the Zometa group, too.)

But Amgen will have to achieve what none of its peers has ever attempted before: getting primary-care physicians comfortable with the idea of injecting a biotech drug into their patients. Denosumab, which will likely carry the brand name Prolia, will be the first nonvaccine biologic product to be marketed to general practitioners. It's a gigantic market where the 29-year-old company has until now been a complete nonplayer. Amgen's biggest products, such as Araesp and Enbrel, are sold to rheumatologists, oncologists, and other specialists. What's more, denosumab is not the type of product patients can inject themselves, so doctors will have to prod them to come into the office twice a year. That could be a hard sell, especially when physicians have the option of prescribing inexpensive pills. Roger Perlmutter, Amgen's vice-president of research and development, isn't worried. "Most elderly people are seeing a doctor every six months anyway," Perlmutter said in a June interview.

Even though Amgen has not yet detailed its marketing plans, it's a safe bet the company will have to hit the airwaves with direct-to-consumer (DTC) ads. Its competitors have been spending heavily on ads for their products: In 2008, Roche spent $92 million on Boniva ads featuring actress Sally Field, according to TNS Media Intelligence. About $60 million of that was spent on TV spots. And Novartis spent $53 million pitching Reclast as the most convenient osteoporosis drug on the market, due to its once-yearly dosing. Perlmutter is quick to point out that Reclast has to be given by IV infusion, making it not quite as convenient as it may appear to be on TV. "General practitioners would have to set up infusion centers," he says. "They won't want to do that. The hassle factor is significant."

Itching for a Blockbuster

Amgen does have some experience with DTC ads, though it hasn't always been positive. In 2005, the FDA asked the company to withdraw ads for Enbrel, a rheumatoid arthritis drug that was also approved to treat psoriasis. The agency felt the psoriasis ads overstated the drug's efficacy and understated its risks. It took eight months for the company to revamp the campaign. And last year, Congressmen John Dingell and Bart Stupak, both Michigan Democrats, looked into whether aggressive advertising of anemia drugs developed by Amgen and marketed both by it and Johnson & Johnson (JNJ) encouraged oncologists to prescribe them in excessive doses. The FDA added "black boxes" to the drugs' labels, warning that they were associated with increased tumor growth.

Such troubles have investors itching for Amgen to prove that denosumab can be its long-awaited next blockbuster. The company's net income grew just 2% last year, to $4.8 billion, on sales that also increased 2%, to $15 billion. But the latest trial results had even the most conservative analysts sitting up and taking notice. Christopher Raymond of Robert W. Baird raised his price target on the stock from 60 to 65. "Dmab," he wrote, invoking the drug's nickname, "hit one out of the park." Soon it may be up to Amgen's marketing staff to follow up with a home run of its own.

[DewDiligence]

(AMGN NVS) The phase-3 denosumab trial in miscellaneous cancer
(i.e. non-breast, non-prostate) showed statsig non-inferiority to Zometa;
however, unlike the phase-3 trial in breast cancer (#msg-39343263), D-mab
missed showing statsig superiority to Zometa by a whisker (p=0.06). The
hazard ratio for the primary endpoint (time to first skeletal event) was
0.84 in the miscellaneous-cancer trial and 0.82 in the breast trial.
(The phase-3 trial of D-mab vs Zometa in HRPC is in progress with data
on the primary endpoint expected in 1Q10.)

As was the case in the breast trial, the miscellaneous-cancer trial had
some cases of the dreaded ONJ side effect, but there was no unbalance
between the D-mab and Zometa arms in the incidence of ONJ.

All told, the miscellaneous-cancer trial is a strong result for AMGN,
although NVS dodged a bullet by the trial’s failure to show statsig
superiority for D-mab.

Denosumab has the tentative brand name, Prolia; the PDUFA date for the
lead indication in osteoporosis is 10/19/09. #msg-39386685 is a good read
on the marketing task that confronts AMGN, assuming FDA approval.

http://finance.yahoo.com/news/Amgen-Announces-Positive-prnews-4099476344.html?x=0&.v=1

›Amgen Announces Positive Top-Line Results for Denosumab in Trial for Delay of Skeletal Related Events in Bone Metastases Patients Compared to Zometa

Second of Three Pivotal Phase Three Bone Metastases Trials Meets Primary Endpoint

Denosumab Delayed Time to Skeletal Related Events

Monday August 3, 2009, 5:03 pm EDT

THOUSAND OAKS, Calif., Aug. 3 /PRNewswire-FirstCall/ -- Amgen (Nasdaq: AMGN ) today announced positive top-line results from a pivotal Phase 3 head-to-head trial evaluating denosumab administered subcutaneously versus Zometa(®) (zoledronic acid) administered as an intravenous (IV) infusion in the treatment of bone metastases in 1,776 advanced cancer patients with solid tumors (not including breast and prostate cancer) or multiple myeloma.

For the primary endpoint, patients treated with denosumab experienced a similar time to first skeletal-related event (SRE) (fracture, radiation to bone, surgery to bone, or spinal cord compression) compared with those receiving Zometa (hazard ratio 0.84, 95 percent CI: 0.71-0.98), which is statistically significant for non-inferiority (p<0.0007). Although numerically greater, the delay in the time to first SRE associated with denosumab treatment was not statistically superior compared to Zometa (adjusted p=0.06) (secondary endpoint). The time to first-and-subsequent SRE was also numerically greater but not statistically superior compared to Zometa (hazard ratio 0.90, 95 percent CI: 0.77-1.04) (secondary endpoint).

Overall, the incidence of adverse events and serious adverse events was consistent with what has previously been reported for these two agents. Rates of osteonecrosis of the jaw (ONJ) were balanced and infrequent in both treatment groups (10 patients receiving denosumab as compared with 11 patients receiving Zometa). Infectious adverse events were balanced between the two treatment arms, as was overall survival and the time to cancer progression.

"We are extremely pleased with these results, which continue to demonstrate that inhibiting RANK Ligand with denosumab provides a clinically meaningful benefit for advanced cancer patients with solid tumors that have metastasized to the bone, and to patients with multiple myeloma, both groups who routinely suffer SREs," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "We are very encouraged by the overall strength of the data, which we will present in a scientific forum later this year. We are also looking forward to reviewing the results of a final SRE study, in patients with advanced prostate cancer, next year."

Bone metastases, the spread of tumors to the bone, are a serious concern for many advanced cancer patients. When cancer spreads to the bone, the growing cancer cells weaken and destroy the bone around the tumor. This damage can result in a number of serious bone complications, collectively called SREs.

Full safety and efficacy data will be submitted for presentation at an upcoming medical meeting in the second half of this year.

Study Design

This was an international Phase 3, randomized, doubleblind, active controlled study comparing denosumab with Zometa in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Patients enrolled in this event-driven study were randomized in a one-to-one ratio to receive either 120 mg of denosumab subcutaneously every four weeks (Q4W) or Zometa administered intravenously at a dose of 4 mg single, 15 minute infusion every four weeks.

In clinical trials thus far to test new medications for bone metastases, treatment success has been measured by whether the bone complications, or SREs, caused by the tumor are reduced or delayed. The primary and secondary endpoints of the denosumab bone metastases studies use a composite endpoint of four SREs - fracture, radiation to bone, surgery to bone, and spinal cord compression - to measure the effectiveness of denosumab versus Zometa.

The primary endpoint was to evaluate if denosumab is non-inferior to Zometa with respect to the first on-study SRE in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma and bone metastases. Secondary endpoints were to evaluate if denosumab is superior to Zometa with respect to the first on-study SRE, as well as first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.

About Denosumab and Amgen's Research in Bone Biology

Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, the essential regulator of osteoclasts (the cells that break down bone). With more than 19,000 patients in trials across indications worldwide, the denosumab development program is the largest ever initiated by Amgen. This broad and deep development program demonstrates Amgen's commitment to researching and delivering pioneering medicines to patients with unmet medical needs. Amgen is studying denosumab in numerous tumor types across the spectrum of cancer induced bone disease. Over 11,000 patients have been enrolled in the denosumab oncology clinical trials testing the drug for bone loss and destruction associated with cancer treatment-induced bone loss in breast and prostate cancers, for the prevention of skeletal related events due to the spread of cancer to the bone in multiple myeloma and multiple solid tumors, and for its potential to delay bone metastases in prostate cancer.

Bone Metastases: Impact and Prevalence

Bone metastases, cancer cells that separate from tumors and migrate to bone tissue where they settle and grow, occur in more than 1.5 million people worldwide. With improvements in cancer care, including earlier diagnosis and new treatment options, leading to increases in survival rates, the number of patients developing metastatic disease secondary to a primary cancer is increasing. Bone metastases are a significant problem for patients with certain types of advanced cancer, with incidence rates of nearly 100 percent in myeloma patients and as high as 75 percent in solid tumor patients.

With bone metastases the growing cancer cells weaken and destroy the bone around the tumor. The damage the tumor has caused to the bone can result in a number of serious complications, collectively called skeletal related events (SREs). These include fracture of a bone, radiation to bone, surgery to bone, or spinal cord compression. All are serious complications for advanced cancer patients.

Regardless of the type of underlying cancer, the process by which cancers invade and destroy bones is fundamentally the same. At the center of this destructive process is a protein RANK Ligand that is stimulated by the presence of cancer in the bone.

The economic burden of U.S. patients with bone metastases is significant and was estimated to be $12.6 billion last year. Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE.

About Amgen

Amgen discovers, develops and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.‹