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Pfizer (PFE) has high hopes for its experimental breast cancer drug palbociclib (PD-0332991), an oral inhibitor of CDK (cyclin-dependent kinases) 4 and 6. The therapy generated excitement among oncologists last December after the drug stopped disease progression for more than two years in 165 patients in a Phase 2 study.

CDK inhibitors have for many years failed in trials, despite a strong mechanistic rationale for their use. Pfizer's success has revived the interest in the concept of blocking cell cycle progression to stop cancer cell growth.

Leerink Swann analyst Seamus Fernandez says palbociclib could generate annual sales of $2.4 billion by 2020 if it is approved for breast cancer, and Barclays Capital is forecasting $2.1 billion in peak sales.

A number of drug companies are now following Pfizer's lead.

After the FDA awarded palbociclib with a breakthrough drug designation, Novartis (NVS) began Phase 1 studies with its own CDK 4/6 drug called LEE011. A Phase 3 trial started recently.

Results were presented at the AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics in October in Boston. LEE011, is claimed by Novartis researchers as a best-in-class contender as a result of the improved science behind it.

Palbociclib could also face competition from LY2835219, a CDK 4/6 drug being developed by Eli Lilly (LLY).

CDK 4 and 6

In many cancers, a tumor suppressor protein called retinoblastoma is deactivated because of an increase in the activity of the proteins CDK 4 and 6. This results in unchecked cell proliferation. CDK4/6 is regulated by cyclin D, whose expression is increased by activation of BRAF and PIK3CA, which are implicated in some melanomas and breast cancers, respectively.

Drugs targeting BRAF and PIK3CA have had success, but most of the treated cancers subsequently develop resistance to the drugs.

Palbociclib

In February Pfizer has initiated a randomized, multi-center, double-blind Phase 3 study evaluating palbociclib in combination with Femara, a drug made by Novartis, versus Femara alone as a first-line treatment for post-menopausal patients with ER+, HER2- locally advanced or metastatic breast cancer.

The Phase 3 trial, with the primary endpoint of PFS (progression-free survival), is aiming to validate the positive trial results with palbociclib plus Femara seen in earlier trials.

ER+ (estrogen receptor positive) means that the cancer cells have a receptor protein that binds the hormone estrogen. ER+ cancer cells may need estrogen to grow, and may stop growing or die when treated with substances that block the binding and actions of estrogen.

HER2- (HER2 negative) means that the breast cancer doesn't have high levels of the protein HER2 as opposed to some breast cancer cells that have a higher than normal level of HER2 on their surface, which stimulates them to grow.

Among post-menopausal patients with advanced breast cancer, ER+, HER2- is the largest subgroup, representing approximately 60 percent of all cases. Despite currently available treatments, survival rates for advanced or metastatic breast cancer remain low.

Femara, the Novartis drug used in the combination, is a hormonal therapy.

In women who have had their menopause, the main source of estrogen is through the conversion of androgens (sex hormones produced by the adrenal glands) into estrogens. This is carried out by an enzyme called aromatase.

Femara blocks the process of aromatisation and so reduces the amount of estrogen in the body. As less estrogen reaches the cancer cells, they grow more slowly or stop growing altogether.

Hormone receptor-positive breast cancers can be treated with hormone therapies. These include tamoxifen and the aromatase inhibitors, Arimidex from AstraZeneca (AZN), Femara or Aromasin made by Pfizer.

Hormone receptor-negative breast cancers are not treated with hormone therapies because they do not have hormone receptors.

In the Phase 3 trial 125mg palbociclib is given to patients orally, once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment. Femara is given in a 2.5 mg dose, orally once daily, continuously.

The trial is conducted at 103 locations, with an estimated enrollment of 450. The trial started in February 2013 and estimated final completion date is March 2016, but partial data will be available before that.

Another Phase 3 trial just began enrolling patients.

In this, palbociclib is combined with fulvestrant, a drug made by AstraZeneca. Fulvestrant, unlike tamoxifen and the aromatase inhibitors, binds competitively to estrogen receptors in breast cancer cells, resulting in estrogen receptor deformation and decreased estrogen binding.

Breakthrough therapy

The breakthrough therapy designation, given to palbociclib by the FDA, was based on preliminary Phase 2 data.

Femara by itself is providing trial patients with additional 7.5 months of PFS, while the combination of palbociclib and Femara more than tripled that level to 26.1 months of PFS. This is considered a dramatic result.

The positive Phase 2 results, which showed the drug was safe, may give Pfizer much of the data it could use in seeking an early ruling, even without the completion of the Phase 3.

If the next round of data is favorable, an early filing could occur, especially since a Phase 3 trial measuring OS (overall survival) is already running.

A little prior history: In 2012 Novartis showed that adding a targeted agent, the mTOR inhibitor Afinitor (everolimus), to hormone therapy could dramatically prolong PFS in relapsed hormone receptor-positive post-menopausal breast cancer.

With the PFS nearly tripling (11.0 versus 4.1 months), the results were regarded as practice-changing, and the idea took hold that adding different targeted agents to early hormone therapy may further enhance the results.

And so palbociclib was tried. The majority of patients enrolled in the palbociclib trial were really sick: they had an aggressive metastatic disease, which underlines the significance of the results.

The fantastic efficacy data is balanced out somewhat by the fact that the CDK inhibitor adds a great deal of hematologic toxicity.

Rates of grade 3/4 neutropenia were increased from 1 to 51 percent and leukopenia from 0 to 14 percent. In the study, 71 percent of the patients required a dose interruption and 35 percent required a dose reduction; adverse events led to 10 percent of discontinuations.

Neutropenia is a low neutrophil count. Neutrophils are a type of white blood cell that help fight off infections. If the neutrophil count falls below a certain level, a patient becomes immunocompromised and faces the risk of serious infections.

But if the dramatic PFS benefit holds up in the Phase 3 study, physicians may be willing to deal with the toxicity. Hormone therapy has always been considered a relatively benign treatment, and physicians usually try to keep women on hormone therapy as long as possible before switching to chemotherapy. While the addition of targeted therapy makes hormone therapy a lot less benign, the efficacy benefits can possibly outweigh the toxicity issues.

LEE011

About Novartis's new compound, LEE011, Dr. William Sellers, global head of oncology at the Novartis Institute for Biomedical Research in Cambridge, MA, said this:

"Chemistry optimization has led to the discovery of LEE011, which, to our knowledge, is the most selective CDK4/6 inhibitor to date. Utilizing the latest cancer genomics data and our knowledge of the role of CDK4/6 activity in the growth of tumor cells, we have identified unique indications and combinations of drugs with LEE011, in which LEE011 demonstrates a robust antitumor activity."

"One of the most notable findings is that, when paired with other targeted agents, LEE011 is often able to prevent the emergence of resistance to the partner compound that would otherwise arise when the partner compound is dosed alone."

Based on the results from preclinical experiments, Novartis has initiated several Phase 1 trials in adults, and a Phase 1 trial in pediatric cancers.

In adults, LEE011 as a single agent is tested in cancers that are dependent on CDK4/6, including liposarcomas, mantle cell lymphomas, and head and neck cancers. In the pediatric trials, LEE011 is tested as a single agent in neuroblastoma and malignant rhabdoid tumors.

Combination studies of LEE011 with other Novartis pipeline drugs are also underway.

Market

Almost 230,000 women in the U.S. will be diagnosed with breast cancer this year, and more than 39,900 will die from it, according to the American Cancer Society.

Palbociclib has good tolerability and a limited adverse event profile. The good tolerability and safety profile is important if the drug is to be used in earlier stages of breast cancer. "Earlier stages" is where a drug like Herceptin, a blockbuster made by Roche, generates most of its sales.

Palbociclib could possibly be appropriate for over 200,000 breast cancer patients in developed markets alone when considering all the different lines of therapy it might work within the HR+ (hormone receptor positive) breast cancer setting.

The HR+ breast cancer market is about three times the size of the HER 2+ setting, from which Herceptin generates most of the approximately $6 billion in annual sales.

Dr. Mikael Dolsten, Pfizer's research head, in a May interview described how the current cancer drugs used in hormonal blockade are sometimes used for many years, and suggested that palbociclib could be used similarly.

Pfizer is also looking at opportunities beyond breast cancer, specifically in melanoma, squamous cell carcinoma, head and neck cancer, lung, esophagus and some hematological cancers but these are opportunities for the future.

Investors' summary

Andrew Baum, a the Citigroup analyst, said that Pfizer in the development of palbociclib is at least two years ahead of its closest competitors, Novartis and Eli Lilly, that are working on similar cancer drugs.

Onyx (ONXX) was part of the palbociclib development process and is entitled to get an 8 percent royalty on worldwide sales if the drug is approved. Amgen (AMGN) has recently bought Onyx.

For the third quarter Pfizer reported EPS (earnings per share) of $0.58, and revenue of $12.64 billion.

The company raised its 2013 guidance of EPS of $2.15-$2.20, versus prior guidance of $2-$2.2 and revenue of $50.8-51.8 billion, versus prior guidance of $50.8-52.8 billion.

Pfizer will pay the next dividend, $0.24 on December 3rd to shareholders of record on November 11.

Cancer-fighting drugs continue to be a priority for Pfizer.

Pfizer chairman and CEO Ian Read has emphasized in the earnings press release the strong sales of cancer drugs Inlyta (a drug that fights late-stage kidney cancer, up 186 percent) and Xalkori (for metastatic non-small cell lung cancer, up 92 percent).

The first wave of cancer drugs, launched last year, included Xalkori, Inlyta and Bosulif. Palbociclib is a bright star in the second wave of cancer drugs, along with dacomitinib.

Dacomitinib, a lung cancer drug, is tested in two ongoing Phase 3 trials. One compares it to Tarceva, a drug made by Roche and the other compares it to Iressa, marketed by AstraZeneca and Teva. The data will be out early next year.

Pfizer also has a PI3K/mTOR inhibitor for endometrial cancer (PF-05212384) and a hedgehog inhibitor (PF-04449913) for hematologic malignancies.

Lipitor, Pfizer's star drug, lost U.S. patent protection in late 2011. In the third quarter sales of Lipitor fell 29 percent to $533 million, as the drug faced generics in more overseas markets.

If just one of the new cancer drugs becomes a blockbuster, bringing in billions of dollars in sales, it could go a long way to replace the loss of billions in Lipitor sales.

Source: Pfizer Vs. Novartis: A New Era In Breast Cancer Treatment