Ibrutinib from Pharmacyclics (PCYC), a Sunnyvale, California-based company, represents a new class of medicines to treat chronic lymphocytic leukemia, or CLL.
The goal is to use the drug without chemotherapy, currently a standard treatment that can be too toxic for some elderly patients.
Ibrutinib is the first drug designed to target Bruton's tyrosine kinase (BTK), a protein that enables abnormal white blood cells to proliferate.
Recently updated results from a Phase 1b/2 clinical trial show that ibrutinib for CLL is highly active and well tolerated in patients who have relapsed and are resistant to other therapies.
Response to the therapy was high across all test groups, with 71 percent of previously untreated older patients experiencing a complete or partial response at either treatment dose (420mg and 840mg).
The same response was observed in 67 percent of the relapsed patients and 50% of the high-risk patient group.
After 22 months of follow-up, the disease had not progressed in 96 percent of previously untreated patients and 76 percent of relapsed and high-risk patients.
In a separate Phase 2 study of 40 patients, ibrutinib worked in combination with Rituxan made by Roche. The drug helped control the cancer in 83 percent of the patients.
Thirty-eight of the 40 patients continued on the therapy without their disease worsening at a follow-up of three to six months.
CLL is the most common form of leukemia, with about 16,000 new cases annually in the U.S. at a median age of 72. About 4,400 Americans die of the disease each year.
CLL originates from white blood cells in bone marrow and can spread to the liver, lymph nodes and spleen, according to the American Cancer Society. The disease may spread for years without any symptoms, and many patients are not treated.
Doctors have found that there seem to be two kinds of CLL.
One kind of CLL grows very slowly, people may survive an average of 15 years or more with it and doctors typically don't treat these patients at all.
The other kind of CLL grows faster and is a more serious disease. People with this form of CLL survive an average of about 8 years and are given a three-drug combination of fludarabine, cyclophosphamide and Rituxan. This can be toxic for elderly patients since chemo attacks cancerous as well as healthy cells.
The leukemia cells from these two types look alike, but lab tests can tell the difference between them. Patients whose CLL cells contain low amounts of ZAP-70 and CD38 proteins have a better prognosis.
Collaboration with Janssen
In December 2011 Pharmacyclics signed a collaboration agreement with Janssen, a Johnson & Johnson (JNJ) company, for the development of ibrutinib.
The collaboration has no fixed expiration date and provides for payments by Janssen to PCYC of a nonrefundable $150 million upon signing, and a potential future milestone payments of up to $825 million, based upon continued development progress ( $250 million ), regulatory progress ( $225 million ) and approval of the product in the U.S. and foreign territories ( $350 million).
Pharmacyclics also has a collaboration deal with Servier, a French company for work on soft tissue sarcoma.
Phase 3 trials
There are several Phase 3 trials in progress.
The Resonate trial evaluates ibrutinib versus ofatumumab (Arzerra, made by Genmab, a Danish company) in patients with relapsed or resistant CLL, or small lymphocytic lymphoma, SLL.
Ibrutinib is used here as a monotherapy, and the primary endpoint is progression-free survival compared to ofatumumab.
The Resonate 2 trial compares ibrutinib to Chlorambucil in patients 65 years of age or older with chronic CLL or SLL who have not been treated before.
Chlorambucil's trade name is Leukeran, made by GlaxoSmithKline (GSK) and it is a chemotherapy drug that can be given orally.
Janssen has initiated the Phase 3 Helios study testing ibrutinib in combination with bendamustine and rituximab in patients with relapsed or resistant CLL or SLL.
Bendamustine is Treanda sold by Teva (TEVA) for treatment of CLL, rituximab is Rituxan from Roche.
The primary endpoint is progression-free survival with ibrutinib versus bendamustine and rituximab therapy alone. Janssen plans to enroll 580 patients worldwide.
Another Phase 3 study by Janssen, the RAY trial is comparing ibrutinib to temsirolimus in patients with relapsed or resistant mantle cell lymphoma who have received one prior line of therapy.
Temsirolimus is Torisel from Pfizer, approved for renal cell carcinoma treatment.
The primary endpoint is progression-free survival. Janssen plans to enroll 280 patients and this trial will take place outside the US.
Mantle cell lymphoma is a rare type of non Hodgkin lymphoma (NHL) and is a cancer of the lymphatic system.
The lymphatic system, similarly to the arteries and veins carrying blood, has tubes that branch through all parts of the body, carrying a colorless liquid called lymph. Lymph circulates around the body tissues and it contains a high number of white blood cells called lymphocytes, which fight infection.
When a person has lymphoma, some of the lymphocytes don't work properly.
There are two types of lymphocytes: B cells and T cells.
Mantle cell lymphoma affects the B cells. The abnormal B lymphocytes start to collect in the lymph nodes or body organs. They can then form tumors and begin to cause problems within the lymphatic system or the organ where they are growing.
In addition to ibrutinib, several new small molecule agents are being developed for treatment of CLL, among them:
- GS-1101, a PI3K inhibitor from Gilead Sciences (GILD)
- IPI-145, another PI3K inhibitor, a drug which should have activity both in B-cell and in T-cell lymphomas, from Infinity Pharmaceuticals (INFI)
- ABT-199, a pill from Abbott (ABT) and Genentech (Roche) which inhibits bcl-2, a protein that deregulates apoptosis in cancer cells. Apoptosis is programmed cell death playing a crucial role in the health of the body by eliminating old cells.
Pharmacyclics currently does not have an approved drug, and has no income from drug sales.
But it has income from Janssen. Most recently it has earned three milestone payments of $50 million each. Together with the upfront payment, the company has now earned $300 million, and with continued clinical and regulatory progress may receive up to an additional $725 million.
PCYC has reported revenue for the fiscal year ended June 30, 2012 $82 million compared to $8.2 million for 2011.
At the end of June the company had cash and cash equivalents of $203.6 million, which compares with $112.3 million at June 30, 2011.
Additionally, the company had $5.8 million due from Janssen Biotech Inc. in connection with its cost-sharing arrangement.
If ibrutinib approved for CLL and other blood cancers, it may generate as much as $5 billion a year, according to Michael Yee, an RBC Capital Markets analyst.
Presumably based on these kind of expectations, the share price had a tremendous run-up this year: it has more than tripled.
But FDA approval may be several years away.
In the past 52 weeks the share price ranged from $12.16 to $70.48. The market cap is $4.10 billion.
This is a promising stock with an overly optimistic valuation.