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Last November the FDA approved Imbruvica, a drug made by Pharmacyclics (NASDAQ:PCYC) and Johnson and Johnson's (NYSE:JNJ) for the treatment of MCL (mantle-cell lymphoma) but the approval was delayed for CLL (chronic lymphocytic leukemia), which is a larger market.

At the time RBC Capital Markets analyst Michael Yee was speculating that the FDA might be waiting for data from the ongoing Resonate trial which compares Imbruvica to Arzerra, a drug made by GlaxoSmithKline (NYSE:GSK).

In January the Phase 3 Resonate trial was stopped early for efficacy at the recommendation of the independent data monitoring board. An interim analysis showed a significant improvement in PFS (progression-free survival) using Imbruvica compared to Arzerra, and the drug also showed an acceptable safety profile.

An FDA decision on Imbruvica's approval for previously treated CLL patients is expected on February 28, as reported by Pharmacyclics' management on the November 7 conference call. The delay is giving Gilead Sciences' (NASDAQ:GILD) CLL candidate idelalisib time to catch up somewhat in the race. Idealisib's Phase 3 trial was also stopped early for good performance and the drug is also waiting for approval.

Idelalisib

The Phase 3 trial showed that idelalisib, Gilead's twice-daily pill, could turn CLL, a deadly blood cancer, into a treatable chronic disease. Dr. Richard R. Furman, the lead investigator of the trial and Associate Professor at Weill Cornell Medical College said:

The treatment today for CLL can be worse than the disease, leading to a great deal of side effects and death. This study, and others we have conducted on idelalisib, demonstrates that we may no longer need to use chemotherapy in CLL. Even if this cancer remains incurable, it now can be treated as if it was a chronic disease with a pill, in the same way that high blood pressure is treated.

CLL is the most common form of leukemia, a cancer of the white blood cells. Some 16,000 Americans are diagnosed with CLL annually, and about 5,000 die of it each year. The prevalence of CLL is approximately 113,000 in the U.S. CLL predominantly occurs in the elderly.

CLL is a cancer of B cells, which normally produce antibodies to fight infections. In CLL, B cells grow out of control, accumulating in all of a patient's organs. When cancer cells are located mostly in the lymph nodes, the disease is called SLL.

Patients are typically treated with a combination of chemotherapeutic drugs, to which they usually respond at first. Unfortunately, the subsequently the cancer comes back and requires repeated cycles of chemotherapy. With each relapse, the remissions become shorter until the patient either no longer responds, or is forced to stop taking the drugs because of their side effects. The side effects are the result of the fact that the medication cannot differentiate between healthy cells and cancer cells.

In the Phase 3 trial the combination of idelalisib and Rituxan, made by Roche (OTCQX:RHHBY) proved overwhelmingly superior to using Rituxan alone. At six months, the CLL in 93 percent of the patients who received the combination therapy had not gotten worse (progression-free survival), compared to 46 percent of patients who received only Rituxan.

The median progression-free survival in the placebo group was 5.5 months, while the median progression-free survival in the idelalisib group had not yet been reached. 81 percent of patients responded to the Rituxan plus idelalisib regimen, compared to 13 percent of those who received Rituxan and a placebo. All responses were partial responses.

The most common side effects in the idelalisib group were fever, fatigue, nausea, chills and diarrhea. In the placebo group, patients most commonly experienced fatigue, cough, nausea and trouble in breathing. So significant were the findings that the study was halted early so all of the participants could receive the idelalisib treatment.

92 percent of patients on the combination therapy were alive after one year of treatment, compared to 80 percent of those who received only Rituxan. The bottom line is that CLL may be treated with idelalisib without toxic chemotherapy. Very few studies in CLL have ever shown improvement in overall survival. The data set also showed the relative ineffectiveness of Rituxan when administered alone in previously treated CLL patients. It improves the white blood cell count for 4-6 months, the nodes shrink a little, then the disease takes off again.

This study will hopefully pave the way for idelalisib to be approved in CLL sometime in 2014. The drug has been granted "breakthrough" designation by the FDA for CLL and has a September 11, 2014 decision date by the FDA in non-Hodgkin's lymphoma.

Imbruvica

The Phase 3 Resonate study included 391 patients at more than 70 sites across 10 countries. The study compared the CD20 antibody Arzerra with Imbruvica at a once daily 420 mg dose over the course of 24 weeks.

Along with improvement in PFS (progression-free survival), the interim analysis also showed significantly better overall survival, a secondary endpoint of Resonate. The patients enrolled in the Resonate study had relapsed or refractory CLL or relapsed or refractory SLL (small lymphocytic lymphoma) with measurable nodal disease. Imbruvica is a first-in-class drug targeting a protein known as BTK (Bruton's tyrosine kinase). BTK is a signaling molecule of the B-cell receptor signaling complex, a pathway that plays a role in the survival of malignant B cells.

An earlier Phase 1b/2 study also showed good results. Results published in June in the New England Journal of Medicine showed response rates of 71 percent with both a 420 mg and a 840 mg dose of the drug. The estimated PFS at 26 months was 75 percent among high-risk and relapsed/refractory patients, and 83 percent of patients remained alive.

Imbruvica is currently investigated in nine different Phase 3 trials in various malignancies including CLL, SLL, mantle-cell lymphoma, and non-Hodgkin's lymphoma. Even though it is approved only for mantle-cell lymphoma at this point, use for other types of cancers is spreading.

Robyn Karnauskus, an analyst at Deutsche Bank, estimated that 35 percent of Imbruvica use is already for CLL, not mantle-cell lymphoma. Although Imbruvica is widely expected to be one of the most important drug launches of the year, some have been disappointed by its sales so far.

Geoffrey Porges, an analyst at investment bank Sanford C. Bernstein, is quoted by the Forbes article, linked above, commented:

Imbruvica was approved on November 13th and IMS has been tracking the first 7 weeks of its launch, with data suggesting sales for November 2013 of around $800,000. The approved indication for Imbruvica is somewhat limiting so far: relapsed patients with the rare B cell malignancy mantle-cell lymphoma (MCL).

Competition

Gazyva, made by Roche, was approved by the FDA in November for CLL in combination with chlorambucil, a chemotherapy agent, made by GlaxoSmithKline .

Updated Stage I results from a Phase 3 trial showed clear and robust activity for Gazyva in combination with chlorambucil compared with chlorambucil alone. PFS (the primary endpoint) was significantly improved, with an 82 percent reduction in risk of progression or death.

Other competitors are lining up as well as there remains a great need for novel therapies for relapsed CLL patients who cannot tolerate chemotherapy. Promising data has been reported during the ASH conference in 2013 about new experimental compounds, including ABT-199 (Abbvie (NYSE:ABBV)/Roche), CTL019 (Novartis (NYSE:NVS)), and IPI-145 (Infinity Pharmaceuticals (NASDAQ:INFI)). Most likely the fiercest adversaries in the CLL market will be idelalisib versus Imbruvica.

The companies set different goals for their agents. Johnson & Johnson hopes that the promising efficacy data with Imbruvica will be repeated in the various ongoing Phase 3 trials and helps Imbruvica become the standard to replace Arzerra in the relapsed setting or to become the key combination partner with chemoimmunotherapy.

Gilead has set the target for idelalisib as an ideal combination partner with chemoimmunotherapy. Both of these targeted therapies are very well-tolerated compared to chemotherapy which makes them lucrative partners or candidates in CLL treatment.

In December analysts at Berstein conducted a survey among 50 hematologists and oncologists about the new drugs and found that the physicians consider Imbruvica and idelalisib for CLL treatment practically interchangeable.

Many physicians will most likely use them in combinations with Rituxan or Gazyva and/or with chemotherapeutic agents. Idelalisib has a slight advantage in that respect since its initial label will contain randomized safety and efficacy data in combination with Rituxan.

Investors' summary

Gilead Sciences will present its fourth quarter and year end 2013 financial results on February 4.

Bloomberg's estimate for 2013 revenue is $10.9 billion and earnings per share is $2.00. The estimate is sourced from 29 analysts. For 2014 the total revenue is projected at $14.5 billion and $3.35 earnings per share. Gilead's move into the cancer arena is full of promise.

The company may not have the experience of a Pfizer, Roche, or Novartis in cancer, but has a vision. The vision is about a future when cancer will no longer be a death sentence but a treatable, manageable chronic disease like HIV.

As DNA sequencing is becoming fast and cheap enough for more doctors to see what's going on with the cancer at a molecular level, patients will be treated with combinations of drugs aimed at specific molecular targets, through convenient oral pills, that offer mild side effects compared to chemotherapy.

As we all know, Gilead is exceptionally good at creating combination pills, therefore this appears to be a realistic vision.

Source: The Leukemia Race: Gilead Vs. Johnson & Johnson, Roche