11/25/2019
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`FDA approves lmbruvica as first therapy for chronic graft-versus-host disease
`
`FDA NEWS PERSPECTIVE
`
`FDA approves lmbruvica as first therapy for
`chronic graft-versus-host disease
`
`August 2, 2017
`
`[ 0 ADD TOPIC TO EMAIL ALERTS
`
`The FDA approved ibrutinib for the treatment of adults with chronic graft-versus-host
`disease who failed prior systemic therapy.
`
`lbrutinib (lmbruvica; Pharmacyclics, Janssen) - a Bruton's tyrosine kinase inhibitor
`already indicated for treatment of certain patients with leukemia, lymphoma and
`Waldenstrom's macroglobulinemia -
`is the first theraP-Y~P-ecifically_aP-P-roved to treat
`chronic GVHD.
`
`typically
`"Patients with chronic GVHD who do not respond to other forms of therapy -
`corticosteroids to suppress their immune system - now have a treatment option
`~P-ecifically indicated to treat their condition," Richard Pazdur, MD, director of the
`FDA's Oncology Center of Excellence and acting director of the Office of Hematology
`and Oncology Products in the FDA's Center for Drug Evaluation and Research, said in
`a press release. 'This approval highlights how a known treatment for cancer is finding
`a new use in treating a serious and life-threatening condition that may occur in
`patients with blood cancer who receive a stem cell transplant."
`
`The FDA based the approval in part on results from the open-label, multicenter, single(cid:173)
`arm PCYC-1129-CA trial, designed to evaluate the efficacy and safety of 420 mg
`ibrutinib once daily for 42 patients with chronic GVHD who failed first-line
`corticosteroid therapy and required additional therapy.
`
`Most patients (88%) had at least two organs involved at baseline, the most common of
`which were the mouth (86%), skin (81%) and gastrointestinal tract (33%).
`
`Twenty-eight patients (67%; 95% Cl, 51-80) achieved a response, with median time to
`response of 12.3 weeks. Researchers observed responses in all organs involved.
`
`Twenty patients (48%) experienced symptom improvement for 5 months or longer.
`
`The most common adverse reactions included fatigue, bruising, diarrhea,
`thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia and
`pneumonia.
`
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`Pharmacyclics Exhibit 2045
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`
`

`

`11 /25/2019
`
`FDA approves lmbruvica as first therapy for chronic graft-versus-host disease
`
`One patient experienced atrial fibrillation .
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`PERSPECTIVE
`
`Chronic GVHD is a major toxicity of bone marrow transplant, which is
`one of the most effective therapies we have for high-risk malignancies.
`Both patients and physicians are reluctant to undertake transplantation,
`not only because of its initial intensity, but because of some of the long(cid:173)
`term toxicities. Even if patients are cured of their leukemia or lymphoma,
`they can end up with this immune-mediated disease that can affect their
`skin, liver, lungs, gastrointestinal tract and joints. When it is severe, it can
`be fatal. It is the dark side of the therapy.
`
`James L.M.
`Ferrara
`
`Despite dozens of trials, nothing has ever worked, in part because we have not had
`good drugs, and in part because the trials are difficult to perform. Patients go home,
`and chronic GVHD may devlop insidiously; it is often initially treated by local
`physicians who do not have experience with chronic GVHD. By the time the patients
`make their way back to the transplant center, chronic GVHD can sometimes be very
`advanced and may not easily respond to therapy. This is one of the most challenging
`scenarios, not only in transplant medicine, but in all of medicine.
`
`We have tried for a long time without making any headway. Steroids, the primary
`treatment, only work in less than half of patients. Further, chronic steroid treatment can
`cause diabetes, bone disease, joint problems and muscle wasting. Other drugs that
`have been investigated have produced responses in approximately one-third of
`patients, usually with inconsistent results.
`
`Studies have now shown that B-lymphocytes that produce antibodies are involved in
`chronic GVHD pathology. lbrutinib blocks a key signaling pathway primarily for B cells,
`including malignant B cells. It has already been FDA approved in diseases such as
`mantle cell lymphoma, lymphocytic lymphoma and chronic lymphocytic leukemia.
`Once we found out these cells were involved in chronic GVHD and the
`pathophysiology, we tried repurposing ibrutinib in this setting.
`
`The results have been remarkable, with two-thirds of patients responding - almost
`one-quarter having complete response and about half having a partial response, many
`lasting for more than 6 months.
`
`https://www .healio.com/hematology-oncology/bone-marrow-transplantation/news/online/% 7B9e5cb 76a-cd54-4f5f-ae24-fa 1284d83a41 % 7D/fda-approv... 2/3
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`

`

`11/25/2019
`
`FDA approves lmbruvica as first therapy for chronic graft-versus-host disease
`
`The FDA approval is based on a small, single-arm trial. But, nothing else has worked,
`and these patients with chronic GVHD who do not respond to steroid treatment are
`often desperate. This is great news for patients.
`
`Because we now have strong evidence that ibrutinib works in chronic GVHD, we may
`be able to move this approach forward to primary treatment. lbrutinib may be one way
`to catch the disease early, improve response rates and avoid some of the serious
`toxicities of steroid treatment.
`
`Disclosures: Ferrara reports he has no relevant financial disclosures.
`
`James L.M. Ferrara, MD, DSc
`The Tisch Cancer Institute at Mount Sinai
`
`https://www.healio.com/hematology-oncology/bone-marrow-transplantation/news/online/% 7B9e5cb76a-cd54-4f5f-ae24-fa1284d83a41 % 7D/fda-approv... 3/3
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