For Immediate Release

Bayer Receives U.S. FDA Breakthrough Therapy Designation for Aliqopa™ (copanlisib) for the Treatment of Marginal Zone Lymphoma

- U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for Aliqopa based on follow-up data from the pivotal Phase II CHRONOS-1 study

- Results showed the efficacy of Aliqopa in patients with indolent non-Hodgkin's lymphoma (iNHL) who have received at least two prior therapies, including patients with relapsed or refractory marginal zone lymphoma (MZL)

- Breakthrough designation aims to facilitate timely development and review of new treatment options for patients with high unmet medical need

- Bayer is conducting two additional Phase III studies - CHRONOS-3 and CHRONOS-4 - to confirm the efficacy and safety of Aliqopa in combination with other therapies in iNHL (including MZL) patients who have relapsed following one or more prior therapies

WHIPPANY, N.J., May 29, 2019 /PRNewswire/ -- Bayer announced today that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for Aliqopa (copanlisib) for the treatment of adult patients with relapsed marginal zone lymphoma (MZL) who have received at least two prior therapies. MZL is an indolent form of non-Hodgkin's Lymphoma (iNHL) and accounts for about 10% of all non-Hodgkin's Lymphoma in the U.S.1

(PRNewsfoto/Bayer)

The Breakthrough Therapy Designation was granted based on data from the MZL subgroup of the pivotal Phase II CHRONOS-1 study, which is the trial that accelerated the U.S. FDA approval of Aliqopa for the treatment of adult patients with relapsed follicular lymphoma (FL) – the most common histological subtype of iNHL – who have received at least two prior systemic therapies. Accelerated approval was granted for this indication based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Aliqopa is an intravenous phosphatidylinositol-3-kinase (PI3K) inhibitor with inhibitory activity predominantly against the PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. The compound is currently not approved by the European Medicines Agency (EMA) or other authorities outside of the U.S.

"The clinical evidence suggests that Aliqopa may address an unmet medical need by providing physicians and MZL patients with a therapy in a relapsed setting," said Dr. Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer's Pharmaceutical Division. "We will continue working closely with the FDA in order to bring Aliqopa to these underserved patients as soon as possible."

The FDA's Breakthrough Therapy Designation is intended to expedite the development and review of drug candidates that treat serious or life-threatening diseases or conditions, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on one or more clinically significant endpoints over available therapies.2

Bayer is conducting two additional Phase III studies – CHRONOS-3 and CHRONOS-4 – to evaluate the efficacy and safety of Aliqopa in combination with other therapies for those with iNHL (including MZL) who have relapsed following one or more prior therapies.  

Clinical Evidence for Aliqopa in Marginal Zone Lymphoma (MZL) 
In the Phase II study 16439 part B (CHRONOS-1), Aliqopa showed preliminary efficacy in indolent non-Hodgkin's lymphoma (iNHL) patients including 23 patients with relapsed or refractory MZL, who have received at least two prior therapies. At the primary analysis, the overall response rate (ORR) of overall iNHL population (n=142) was 59.2%, while MZL patients was 69.6% (n=23).  An 18 month follow-up analysis of CHRONOS-1 showed an ORR in the full analysis set (FAS) population of 60.6% and in the MZL histology an ORR of 78.3% (n=23). The most common treatment emergent adverse events (experienced by greater than or equal to 20% of the MZL subgroup) were hyperglycemia and fatigue (47.8%), hypertension and diarrhea (43.5%), nausea (26.1%), pyrexia and cough (21.7%). The most common worst Grade 3 TEAEs were hypertension (39.1%) and hyperglycemia (34.8%).

About MZL 
MZL is an indolent form of non-Hodgkin's Lymphoma (iNHL) and accounts for about 10% of all non-Hodgkin's Lymphoma in the U.S.1 Typically chemotherapy and/or immunotherapy are often chosen for the treatment of MZL. While initial therapies are often successful, there continues to be an unmet need for relapsed (advanced) MZL.

About Aliqopa (copanlisib) Injection
Aliqopa (copanlisib) is indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Aliqopa is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. 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.

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 for Aliqopa (copanlisib) Injection

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.

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.

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.

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.

Achieve optimal blood glucose control before starting each ALIQOPA infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia.

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.

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.

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.

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.

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.

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%).

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

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.

Please see the full Prescribing Information of Aliqopa (copanlisib) Injection.

About Oncology at Bayer  
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes five marketed products and several other assets in various stages of clinical development. Together, these products reflect the company's approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

About Bayer 
Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to benefit people by supporting efforts to overcome the major challenges presented by a growing and aging global population. At the same time, the Group aims to increase its earning power and create value through innovation and growth. Bayer is committed to the principles of sustainable development, and the Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2018, the Group employed around 117,000 people and had sales of 39.6 billion euros. Capital expenditures amounted to 2.6 billion euros, R&D expenses to 5.2 billion euros. For more information, go to www.bayer.us.

© 2019 Bayer  
BAYER®, the Bayer Cross and Aliqopa are registered trademarks of Bayer.

Media Contact:    
Rose Talarico, Tel. +1 862.404.5302 
E-Mail: rose.talarico@bayer.com 

Forward-Looking Statements  
This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer's public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

References

  1. NCCN, (2016) NCCN Clinical Practice Guidelines in Oncology (NCCN): NonHodgkin's Lymphomas.
  2. Food and Drug Administration, Fact Sheet: Breakthrough Therapies: https://www.fda.gov/regulatory-information/food-and-drug-administration-safety-and-innovation-act-fdasia/fact-sheet-breakthrough-therapies (accessed May 2019)
  3. AliqopaTM (copanlisib) for injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, September 2017.

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