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When on February 24, 2012, we wrote that the Pharmacyclics (NASDAQ:PCYC) story is one of only a few in which the power of the firm’s product pipeline overshadows the stock market’s technical influence, we were not hallucinating, as some have claimed. With this firm’s drug ibrutinib (PCI-32765) demonstrating safety and efficacy in various blood cancers, negative unsubstantiated speculations failed to persuade investors to cease investing in PCYC. Trial results have confirmed the superiority of ibrutinib in treating B-cell cancers, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM).

What is going on now with ibrutinib is a déjà vu phenomenon. Similar announcements of promising data have been narrated in the past about a few other breakthrough blockbuster targeted cancer drugs, including Idec’s drug Rituxan (rituximab), Genentech’s drug Herceptin (trastuzumab), and a few other therapeutic molecules developed by firms that were small at the time. Surprisingly, the small firms generated billions of dollars in revenues before and after being acquired for billions of dollars. During early phases of Rituxan’s development, while the oncology and immunology communities were thrilled with the drug’s outstanding performance and potential, Wall Street was skeptical. Investors’ disbelief was not driven by inaccuracies in the data, but simply by the fact that Idec was a small biotech firm, which automatically labeled it as a very high risk for investment. Rituxan, though, was granted FDA approval in 1997. It immediately became a best seller and remained a blockbuster, generating billions of dollars in revenues. Like ibrutinib, Rituxan is being used in the treatment of lymphomas, leukemias, and autoimmune diseases. Rituxan is also effective for prevention of organ transplant rejection.

Targeting Bruton’s Tyrosine Kinase (Btk)

Ibrutinib is the first and most advanced drug designed to inhibit Bruton’s tyrosine kinase, an important cell-signaling enzyme on blood cells, including B-cells. Being a crucial part of the B-cell receptor (BCR) signaling pathway, its activation contributes to the thriving of many types of B-cell cancers. Blocking Btk could halt cancer proliferation, disrupt tumor cell adhesion, and cause cancerous B-cells to commit suicide (apoptosis). Blocking Btk has, indeed, halted cancers. Moreover, it inhibited the recruitment and function of other immune cells, including monocytes, macrophages and mast cells. Preclinical animal studies demonstrated that ibrutinib reduces circulating autoantibodies, thus, the drug is expected to also reverse the course of arthritis and other autoimmune diseases and allergic diseases. As a matter of fact, the drug has demonstrated it prevents the occurrence of kidney disease in a mouse model of systemic lupus erythematosus (SLE).

At ASCO, clinical trial results continued to confirm previous promising results. In Phase 1 and Phase 2 clinical trials on a variety of B-cell malignancies, ibrutinib demonstrated substantial efficacy and favorable safety profile in chronic lymphocytic leukemia (CLL) and a number of non-Hodgkin’s lymphoma (NHL) subtypes, mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Adverse effects anticipated based on the drug’s inhibition of Btk did not materialize.

Data from Phase 1b/2 trials with ibrutinib as single agent on chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) confirmed the drug’s safety and efficacy in treatment-naïve patients. In combination with ofatumumab (Arzerra) on patients with chronic lymphocytic leukemia/small lymphocytic leukemia/prolymphocytic leukemia (CLL/SLL/ PL) and Richter transformation, results demonstrate that the combination was well-tolerated and highly active in patients with heavily pretreated relapsed/refractory CLL/SLL. The drug is described to have a rapid onset of response, low relapse rate, and favorable safety profile.

1. PLL is a type of chronic lymphocytic leukemia (CLL) in which too many immature white blood cells (prolymphocytes) are found in the blood and bone marrow. PLL usually progresses more rapidly than classic CLL. It is also called prolymphocytic leukemia.

2. Richter's transformation, or Richter's syndrome (RS), is a complication of B-cell CLL or hairy cell leukemia (HCL) in which the leukemia changes into a fast-growing diffuse large B-cell lymphoma. There is also a less common variant in which the CLL changes into a Hodgkin’s lymphoma.

Similar positive results were achieved thus far in a phase 1b/2 trial of ibrutinib in combination with bendamustine (Treanda) and rituximab (Rituxan) in patients with relapsed and refractory CLL. With a median follow up of 8.1 months, two patients out of 30 patients in the trial reported progressive disease and five patients proceeded to stem cell transplant. Twenty-three patients (77%) remain in the study. Overall response rate (ORR) was 93%, with 13% of patients achieving a complete response with no morphologic evidence of CLL. No new safety concerns were identified with the combination. There have been no discontinuations due to adverse events.

In patients 65 years of age or older, results of a single-agent, multi-cohort study evaluating ibrutinib in CLL/SLL with relapsed/refractory disease or with treatment-naive disease demonstrate the daily 420mg oral dose was well tolerated. The discontinuation of treatment for adverse events occurred in three of 83 patients and the side effects, diarrhea, nausea/vomiting and dyspepsia were the most frequently reported and were of modest severity. Significant neutropenia and thrombocytopenia were uncommon with the 420mg dose, but were more frequently observed in patients taking the 840mg dose in spite of the shorter follow-up. A characteristic pattern of response in the CLL patients was rapid reduction of lymph node disease and initial lymphocytosis. The resolution of lymphocytosis was more rapid in treatment-naive versus relapsed/refractory patients.

With the 420mg regimen in treatment-naive disease:

At a median follow-up of 6.3 months; Overall objective response: 67%. Nodal response: 19%

With a median follow-up of 7.8 months in the cohort of relapsed/refractory patients treated with 420mg: Overall objective response: 48% Nodal response: 41%

With a median follow-up of 14.4 months: Overall response rate: 81% Progression-free survival (PFS): 96%.

Twelve percent of patients achieved a complete response with no morphologic evidence of CLL. The majority of adverse events were grade 2 or lower. Of the 31 patients in the trial, only one has discontinued due to disease progression.

To see Pharmacyclics presentations at ASCO 12 click here.

In August 2011, Pharmacyclics entered into a five-year Cooperative Research and Development Agreement with the National Cancer Institute (NCI) for the development of ibrutinib. Under the agreement, the NCI's Division of Cancer Treatment and Diagnosis will sponsor Phase 1 and Phase 2 trials of PCI-32765 in various hematologic malignancies.

At the ASCO meeting, Louis M. Staudt, M.D., Ph.D, Deputy Chief of the Metabolism Branch of the National Cancer Institute who presented early results from a Phase 2 trial of ibrutinib in diffuse large B-cell lymphoma (DLBCL) said, “Ibrutinib, is the culmination of more than a decade of basic research genomic studies and studies of the molecular biology of these aggressive tumors, which led us to pinpoint rational targets." He observed, “One of the insights gleaned from that basic research is that what gets diagnosed as diffuse B cell lymphoma is actually an amalgam of three molecularly distinct diseases."

Preliminary results from an ongoing Phase 2 study suggest that ibrutinib can bring positive efficacy results in some patients with the diffuse large B-cell lymphoma (DLBCL), including those with chemotherapy-refractory disease. Dr. Staudt explained that DLBCL accounts for about 40% of non-Hodgkin's lymphomas, which makes it the most common subtype of the disease, for which half of the patients have no treatment. Chemotherapy and rituximab offer cures for only half of DLBCL patients. He went on to say, “The activated B-cell (ABC) subtype has the poorest clinical outcome with current drugs. Genetic studies found that receptors on the surface of B cells play an important role in the progression of this lymphoma subtype. In normal B cells, these B-cell receptors help the cells recognize infections, but in malignant B cells in ABC lymphomas, they provide signaling that promotes tumor survival. More than 20% of ABC tumors have mutations that alter the activity of the B-cell receptor.”

Among other discoveries is that Bruton's tyrosine kinase is essential to maintain the survival of ABC lymphoma cells. Based on the molecular research, the investigators testing ibrutinib determined that the drug is an irreversible inhibitor of Btk. "It makes a stable bond with the Btk enzyme, so it is irreversible.” In a pilot study of 10 patients resistant to other treatments given single-agent ibrutinib, there were two complete responses, one partial response, and one case of stable disease. One patient continues to be in complete remission after 15 months.

In the ongoing Phase 2 multi-center trial with a higher dose, so far 10 of about 50 patients have completed treatment with one complete response and three partial responses. One patient has stable disease. Ibrutinib was well tolerated without significant side effects. Treatment-related toxicities include Grade 1 diarrhea, Grade 1 nausea, and Grades 1–2 fatigue. "It has a wonderful side effects profile that will allow it to be combined with other agents," Dr Staudt said.

With regard to Multiple Myeloma (MM), internal and external pre-clinical studies suggested a vital role for Btk in both malignant plasma cells and osteoclasts, the principal effectors of the bone complications of multiple myeloma. Based on these data, researchers believed that Btk represents a viable therapeutic target in MM, and Phase II trial of ibrutinib is now ongoing.

The story of ibrutinib has not ended yet. Many trials on all the aforementioned cancers are ongoing with ibrutinib as a single agent and in combination treatments. So far, the results are promising and the expectations are very high.

Product Pipeline

In 2006, Pharmacyclics acquired multiple small molecule drug candidates for the treatment of cancer and other diseases from Celera Genomics, an Applera Corporation business (now Celera Corporation – a subsidiary of Quest Diagnostics Incorporated), including technology and intellectual property relating drugs that target histone deacetylase (HDAC) enzymes, selective HDAC enzymes, a Factor VIIa inhibitor targeting a tumor signaling pathway involved in angiogenesis, tumor growth and metastases, and B-cell associated tyrosine kinase inhibitors potentially useful for the treatment of lymphomas and autoimmune diseases.

The firm has three product candidates in clinical development and several preclinical molecules in lead optimization. The drug candidates are small-molecule enzyme inhibitors, targeting key biochemical pathways of diseases with critical unmet needs. They include the Bruton’s tyrosine kinase (Btk) inhibitor ibrutinib currently in clinical trials for various hematologic malignancies; a Btk inhibitor lead optimization program targeting autoimmune indications, an inhibitor of Factor VIIa (PCI-27483) in a Phase 2 clinical trial for pancreatic cancer and a histone deacetylase (HDAC) inhibitor (PCI-24781) in Phase 1 and 2 clinical trials for solid tumors and hematological malignancies.

Final word: Pharmacyclics’ uninterrupted stock rally is not based on investors unsubstantiated great speculations, but on ibrutinib’s data from chronic lymphocytic leukemia, small lymphocytic leukemia, mantle cell lymphoma and diffuse large cell lymphoma. The drug is also promising as a treatment for autoimmune diseases. The rest of the pipeline is also showing early promises. Again, we stress, ibrutinib is very promising and has the chance to generate more revenues than Rituxan. The drug is seen as a game-changer.

We hope the rest of the trials confirm the previous results and validate the hopes. In the meantime, Pharmacyclics has made huge steps toward better understanding B cell malignancies and advancing the treatment of these cancers. Is this not the utmost of what we expect from the biotechnology industry?

Disclosure: Long PCYC.

Source: Pharmacyclics: Product Pipeline Overshadows Stock Market Influence