Building on positive trial data in a range of blood cancers, Pharmacyclics Inc./Johnson & Johnson’s ibrutinib has received a third breakthrough therapy designation from FDA, this time for chronic lymphocytic leukemia with a deletion of the chromosome 17, the firms announced April 8.

CLL is the most common kind of leukemia in adults, with some 16,000 new cases each year and 113,000 living with the disease in the U.S., according to the company. Those with deletion of the short arm of chromosome 17 (del 17p) – about 7% of treatment-naïve patients and 20% to 40% of relapsed patients – are resistant to treatment and have the worst prognosis.

Breakthrough therapy announcements for Pharmacyclics’ ibrutinib and Pfizer’s palbociclib coincide with the AACR meeting in D.C.

The designation allows access to a new approval pathway established by the FDA Safety and Innovation Act to speed development of drugs that offer dramatic medical advances over existing therapy, based on early clinical evidence. In February, FDA granted breakthrough designation to ibrutinib for two uncommon B-cell malignancies: relapsed/refractory mantle cell lymphoma and Waldenstrom’s macroglobulinemia ([A#14130213001]).

A first-in-class inhibitor of Bruton’s tyrosine kinase (BTK), a key signaling enzyme for B-cell cancers, ibrutinib demonstrated good results in trials of a number of blood cancers, including CLL, diffuse large B-cell lymphoma with the hard-to-treat ABC subtype, follicular lymphoma and mantle cell lymphoma, at the 2012 annual American Society of Hematology meeting Also see "Ibrutinib Results Suggest Potential To Shake Up CLL Market" - Pink Sheet, 17 December, 2012.. J&J declined to comment on whether other breakthrough therapy requests for ibrutinib are pending with FDA.

FDA has granted a total of 11 breakthrough designations so far, of which seven have been publicly announced by sponsors (see chart,[A#00130415013]).

Pfizer Inc. announced on April 10 that its breast cancer drug palbociclib (PD-03392991) received breakthrough designation based on interim results from a Phase II study released in December Also see "Pfizer Breast Cancer Drug Could Fill Void Left By Avastin Withdrawal" - Pink Sheet, 5 December, 2012.. In this trial, the oral CDK 4/6 inhibitor demonstrated a marked improvement in progression-free survival in combination with the aromatase inhibitor letrozole compared to letrozole alone in advanced estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. Palbociclib is now being tested in a first-line Phase III study in the same population.

Positive Ibrutinib Data At AACR

The breakthrough therapy announcements coincided with the American Association of Clinical Research meeting, held in Washington, D.C. from April 6-10. At the meeting, ibrutinib was featured in nine presentations, including eight preclinical studies in a variety of cancers and one clinical trial in CLL that was funded by the National Heart, Lung and Blood Institute.

The NHLBI’s Phase II CLL study tested ibrutinib as a monotherapy in 53 patients with untreated or relapsed/refractory disease, including 29 with del 17 p status and 24 who were over the age of 65 (older patients are harder to treat with conventional therapies). Investigators evaluated patients after six months and every six months subsequently until disease progression.

Ibrutinib was highly effective regardless of 17p status, with a partial response rate of 52% overall, investigators reported. Furthermore, after six months of treatment, lymph node size was reduced by 95% and spleen size shrunk in all participants. In the roughly half of patients who had a bone marrow biopsy, tumor infiltration decreased by 82%. Responses were durable, with an estimated event-free survival rate at 12 months of 94%.

The study confirms ibrutinib’s single-agent anti-leukemia activity and suggests targeted therapy is “becoming a reality” in CLL, investigator Adrian Wiestner, head of the lymphoid malignancies section at the NHLBI, said in an AACR statement on April 8.

Results from the NHLBI study are encouraging in that they confirm previous research in treatment-naïve people and bode well for the pivotal RESONATE-2 study of ibrutinib against chlorambucil in elderly, treatment-naïve CLL patients, JMP Research’s Michael King commented in an April 8 note.

Pharmacyclics’ Ibrutinib Scoops Another FDA Breakthrough Designation, And Pfizer Joins The Club

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