Bayer Receives FDA Approval for Aliqopa™ (copanlisib) 60 mg vial for Injection in Adults with Relapsed Follicular Lymphoma after Two Prior Systemic Therapies

- Accelerated approval based on overall response rate (ORR) of 104 adult patients with relapsed follicular lymphoma (FL) from the Phase II CHRONOS-1 study(1)

- Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(1)

- Aliqopa achieved a 59% ORR in patients with relapsed FL [n=104 (95% CI 49, 68)](1)

- First approval of an intravenous phosphatidylinositol-3-kinase (PI3K) inhibitor (1)

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Bayer

Sep 14, 2017, 17:10 ET

WHIPPANY, N.J., Sept. 14, 2017 /PRNewswire/ -- Bayer announced today that the U.S. Food and Drug Administration (FDA) has approved Aliqopa^™(copanlisib) for the treatment of adult patients with relapsed FL who have received at least two prior systemic therapies.¹ Accelerated approval was granted for this indication based on ORR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.¹

Aliqopa is a novel intravenous PI3K inhibitor with inhibitory activity predominantly against the PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells.¹ The FDA granted approval under the accelerated approval pathway based on data from the open-label, single-arm Phase II CHRONOS-1 [NCT01660451] trial investigating Aliqopa in 104 adult patients with follicular B-cell non-Hodgkin's lymphoma (NHL) who had relapsed disease following at least two prior systemic therapies.¹

FL is the most common subtype of indolent, or slow-growing, NHL, comprising approximately one out of five lymphomas in the U.S.^2,3 Response rates and duration of response decline with each line of therapy, underscoring the need for patients whose disease has already progressed.

"Before the approval of Aliqopa, doctors and patients facing follicular lymphoma, a very serious and difficult-to-treat blood cancer, have had a need for new and effective options when patients relapse," said Carsten Brunn, Head of Bayer Pharmaceuticals, Americas Region. "The FDA's accelerated approval of this important treatment reflects Bayer's commitment to delivering new treatment options, and we commend the FDA on its speedy review and ongoing dedication to innovation in areas of great unmet medical need."

"When treating patients with relapsed follicular lymphoma, two factors for physicians involve lessening tumor burden and reducing adverse events patients may experience from treatments. Therapies need to be both effective and tolerable," said Dr. Anas Younes, Medical Oncologist and Chief of Lymphoma Service at Memorial Sloan Kettering Cancer Center. "The PI3K pathway is activated in many tumor types, including lymphoma, and targeting PI3K therapeutically is a very important strategy in this area of disease. Copanlisib has a safety and efficacy profile that is a welcome advance for both doctors and patients in third-line follicular lymphoma."

Aliqopa is associated with the following Warnings and Precautions: serious, including fatal, infections, Grade 3 or 4 hyperglycemia, Grade 3 hypertension, non-infectious pneumonitis (NIP), Grade 3 or 4 neutropenia, Grade 3 or 4 cutaneous reactions, and embryo-fetal toxicity. Please see the full Important Safety Information below.

Developed by Bayer, Aliqopa is the only approved PI3K inhibitor with inhibitory activity predominantly against PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells.¹ It is also the only one to be administered intravenously on an intermittent schedule.¹

"Today's approval of copanlisib marks an important advance in the development of new treatment options for adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies," said Meghan Gutierrez, Chief Executive Officer of the Lymphoma Research Foundation. "This approval provides another option for patients; we commend the patients and investigators who enable research such as this to continue to push forward to ultimately move closer to finding a cure."

The New Drug Application for Aliqopa received priority review, which is reserved for medicines that would provide significant improvements in the safety or effectiveness of the treatment of serious conditions. The product was approved under FDA regulations 21 CFR Part 314 Subpart H (accelerated approval). The FDA had previously granted Aliqopa fast track designation in FL as well as Orphan Drug designation for the treatment of patients with FL and for the treatment of splenic, nodal, and extranodal subtypes of marginal zone lymphoma.

Aliqopa will be available in the U.S. market immediately. The Aliqopa™ Resource Connections (ARC^TM) Program, which is dedicated to supporting patients on their treatment journey and includes a range of resources to help navigate the insurance process and identify sources of financial assistance, is now available. The program offers free medication to those who are uninsured or underinsured and meet the eligibility criteria, and includes a $0 Co-Pay Program for covered patients. For more information, visit www.aliqopa.com.

Efficacy and Safety Data Supporting Aliqopa Approval

The Phase II CHRONOS-1 (ClinicalTrials.gov Identifier: NCT01660451) trial included 104 subjects with follicular B-cell NHL who had relapsed disease following at least two prior systemic therapies.¹ In the trial, copanlisib achieved an ORR of 59% [n=104 (95% CI 49, 68)], with 14% of patients achieving a complete response, and a median duration of response of 12.2 months (0+, 22.6).¹ Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed ORR.

Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most frequently observed adverse drug reactions (≥20%) in copanlisib-treated patients were: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%).¹ The safety data reflect exposure to copanlisib in 168 adults with follicular lymphoma and other hematologic malignancies treated with copanlisib 60 mg or 0.8 mg/kg equivalent in clinical trials. Patients with small lymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia and marginal zone lymphoma were also enrolled in the study and included in the safety analysis.

About Follicular Lymphoma

FL is the most common indolent form of B-cell NHL, accounting for approximately 20 to 30 percent of all NHLs.^2,4 FL is typically a slow-growing, or indolent, form of NHL, in which the cancer cells grow in a circular pattern in lymph nodes.³ Often, FL presents with no obvious symptoms of the disease at diagnosis; however, some common symptoms may include enlarged lymph nodes in the neck, armpits, abdominal area or groin, fatigue, shortness of breath, night sweats or unexplained weight loss.⁵ Relapse is common, although remission may last for years.⁶

About Aliqopa

Aliqopa is an inhibitor of PI3K with inhibitory activity predominantly against PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells.¹ The PI3K pathway is involved in cell growth, survival and metabolism, and its dysregulation plays an important role in FL. Aliqopa has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Aliqopa inhibits several key cell-signaling pathways, including B cell receptor signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.¹ Aliqopa is administered as a 1-hour intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule. Treatment should be continued until disease progression or unacceptable toxicity.¹

The broad clinical development program for copanlisib also includes ongoing Phase III studies in indolent NHL (iNHL) patients who have relapsed or are refractory to prior therapies. The CHRONOS-3 Phase III study is evaluating copanlisib in combination with rituximab in relapsed iNHL and the CHRONOS-4 Phase III study is evaluating copanlisib in combination with standard immunochemotherapy in relapsed iNHL. More information about these trials can be found at www.clinicaltrials.gov.

Important Safety Information

Infections: Serious, including fatal, infections occurred in 19% of 317 patients treated with ALIQOPA monotherapy. The most common serious infection was pneumonia. Monitor patients for signs and symptoms of infection and withhold ALIQOPA for Grade 3 and higher infection.¹

Serious pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of 317 patients treated with ALIQOPA monotherapy. Before initiating treatment with ALIQOPA, consider PJP prophylaxis for populations at risk. Withhold ALIQOPA in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis.¹

Hyperglycemia: Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with ALIQOPA monotherapy. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with ALIQOPA may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after ALIQOPA infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment.¹

Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with ALIQOPA following adequate glucose control and should be monitored closely. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia.¹

Hypertension: Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with ALIQOPA monotherapy. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with ALIQOPA may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on Cycle 1 Day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the ALIQOPA infusion. Optimal BP control should be achieved before starting each ALIQOPA infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hypertension.¹

Non-infectious Pneumonitis: Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy. Withhold ALIQOPA and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by ALIQOPA have been managed by withholding ALIQOPA and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of non-infectious pneumonitis.¹

Neutropenia: Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with ALIQOPA monotherapy. Serious neutropenic events occurred in 1.3%. Monitor blood counts at least weekly during treatment with ALIQOPA. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of neutropenia.¹

Severe Cutaneous Reaction: Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with ALIQOPA monotherapy respectively. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of severe cutaneous reactions.¹

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg/day (4.5 mg/m² /day body surface area) corresponding to approximately 12% the recommended dose for patients. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least one month after the last dose.¹

Lactation: Advise women not to breastfeed. Advise a lactating woman not to breastfeed during treatment with ALIQOPA and for at least 1 month after the last dose.¹

Adverse Drug Reactions: Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most frequently observed adverse drug reactions (≥20%) in ALIQOPA-treated patients were: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%).¹

Drug Interactions: Avoid concomitant use with strong CYP3A inducers. Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors.¹

Please see the full Prescribing Information.

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¹Aliqopa^TM (copanlisib) for injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, September 2017.
²Cancer.net. Lymphoma – Non-Hodgkin: Subtypes. http://www.cancer.net/cancer-types/lymphoma-non-hodgkin/subtypes. Accessed September 2017.
³American Cancer Society. Types of Non-Hodgkin Lymphoma. https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/types-of-non-hodgkin-lymphoma.html. Accessed September 2017. ⁴Lymphoma Research Foundation. Indolent Follicular Lymphoma. http://www.lymphoma.org/atf/cf/%7B0363cdd6-51b5-427b-be48-e6af871acec9%7D/INDOLENT%20FOLLICULAR.PDF. Accessed September 2017.
⁵American Cancer Society. 2017 Cancer Facts & Figures. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. Accessed September 2017. ⁶Lymphoma Research Foundation. Follicular Lymphoma. 2017. http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300155. Accessed September 2017.