• Farydak (panobinostat) combination improved PFS by 7.8 months for patients who received >=2 prior regimens including bortezomib and an IMiD[1]
• Farydak would be the first HDAC inhibitor with epigenetic activity to treat multiple myeloma[2],[3]
• CHMP positive opinion marks a key milestone toward panobinostat availability in the EU, aligning with recent US FDA approval

Basel, Switzerland (Press Release) – The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for Farydak® (panobinostat, pre­vi­ously known as LBH589) capsules, in com­bi­na­tion with bor­tez­o­mib[*] and dex­a­meth­a­sone, for the treat­ment of adult patients with re­lapsed and/or refractory multiple myeloma who have received at least two prior regi­mens in­­clud­ing bor­tez­o­mib and an immuno­modu­la­tory agent (IMiD). If approved in the EU, panobinostat will be first in its class of anticancer agents avail­able to these patients[1].

Multiple myeloma is a cancer of the plasma cells, a type of white blood cell present in the bone marrow, and affects approx­i­mately 84,000 people in Europe[4],[5]. Panobinostat is the first histone deacetylase (HDAC) inhibitor to show efficacy in multiple myeloma[2]. As an HDAC inhibitor, its epigenetic activity may help re­store cell function in patients with multiple myeloma[3].

"Panobinostat is the first and only HDAC inhibitor recommended by the CHMP for the treat­ment of patients living with multiple myeloma who have progressed after standard-of-care ther­apy with bor­tez­o­mib and an IMiD," said Alessandro Riva, MD, Global Head of Oncology Development and Medical Affairs, Novartis Oncology. "We are pleased with the positive CHMP opinion on panobinostat for pre­vi­ously treated patients because it brings us one step closer to providing a new treat­ment option for patients in need in Europe."

The CHMP recom­men­da­tion is based on efficacy and safety data in a subgroup analysis of 147 patients who had received at least two prior regi­mens, in­­clud­ing bor­tez­o­mib and an IMiD, during the Phase III, ran­dom­ized, double-blind, placebo-controlled, multi­center global registration trial, called PANORAMA-1 (PANo­bino­stat ORAl in Multiple MyelomA), eval­u­ating panobinostat in com­bi­na­tion with bor­tez­o­mib and dex­a­meth­a­sone against bor­tez­o­mib and dex­a­meth­a­sone alone in patients with re­lapsed and/or re­lapsed and refractory multiple myeloma. The trial found that the median pro­gres­sion-free survival (PFS) benefit in­­creased in panobinostat patients who had received prior treat­ment with both bor­tez­o­mib and an IMiD (12.5 months; n=73), as compared to the placebo arm (4.7 months; n=74) (hazard ratio=0.47 [95% con­fi­dence in­ter­val (CI): 0.31, 0.72])[6].

The most common non hema­to­logical adverse reac­tions in­cluded diarrhea, fatigue, nausea and vomiting. Treatment-emergent hema­to­logical toxicities in­cluded thrombo­cytopenia, anemia, neu­tro­penia and lymph­o­penia. QTc prolongation of >480 and <500 msec was recorded in 1.3% of patients and change from base­line of >60 msec was observed in 0.8% of patients. No patients had an absolute QTc prolongation of >500 msec. Cardiac events (most frequently atrial fibrillation, tachycardia, palpitation and sinus tachycardia) were re­ported in 17.6% of the panobinostat-treated patients versus 9.8% of placebo-treated patients and syncope events were re­ported in 6.0% versus 2.4%. Discontinuation due to adverse events (AEs), re­gard­less of causality, was observed in 36.2% of patients. The most common AEs leading to treat­ment dis­con­tinu­a­tion were diarrhea (4.5%), asthenia and fatigue (2.9% each) and pneu­monia (1.3%). On treat­ment deaths not due to the study indi­ca­tion (multiple myeloma) were re­ported in 6.8% of panobinostat-treated patients versus 3.2% of placebo-treated patients[6].

In the EU, the European Com­mis­sion generally follows the recom­men­da­tion of the CHMP and delivers its final de­ci­sion within three months of the CHMP recom­men­da­tion. The de­ci­sion will be appli­­cable to all 28 EU member states plus Iceland, Norway and Liechtenstein. Additional regu­la­tory sub­missions for panobinostat are being reviewed by health author­i­ties world­wide. Panobinostat in com­bi­na­tion with bor­tez­o­mib and dex­a­meth­a­sone was approved in the US in February 2015 and Chile in May 2015 under brand name Farydak® for the treat­ment of patients with multiple myeloma who have received at least two prior regi­mens, in­­clud­ing bor­tez­o­mib and an IMiD. Continued approval for this indi­ca­tion may be contingent upon veri­fi­ca­tion and description of clin­i­cal benefit in con­firmatory trials[7].

About multiple myeloma

Multiple myeloma impacts approx­i­mately 84,000 people in Europe[5]. Multiple myeloma is a cancer of the plasma cells, a kind of white blood cell present in bone marrow-the soft, blood-producing tissue that fills the center of most bones. The cancer is caused by the pro­duc­tion and growth of ab­nor­mal cells within the plas­ma, which multiply and build up in the bone marrow, pushing out healthy cells and preventing them from func­tioning normally[4]. Multiple myeloma is an incurable disease with a high rate of relapse (when the can­cer returns) and resistance (when the ther­apy stops work­ing)[8]. Standard-of-care regi­mens of pro­te­a­some inhibitors and IMiDs are often used to treat multiple myeloma, but most patients will stop responding to these treat­ments creating an unmet need for new options with novel mech­a­nisms of action[8],[9],[10]. Multiple myeloma typically occurs in individuals 60 years of age or older, with few cases in individuals younger than 40[11].

About the PANORAMA Clinical Trial Program

PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) is a Phase III ran­dom­ized, double-blind, placebo-controlled, multi­center global registration trial to eval­u­ate panobinostat in com­bi­na­tion with bor­tez­o­mib and dex­a­meth­a­sone against bor­tez­o­mib and dex­a­meth­a­sone alone in patients with re­lapsed or re­lapsed and refractory multiple myeloma who failed on at least one prior treat­ment. The study of 768 patients took place in 215 clin­i­cal trial sites world­wide making it the largest global registration trial for multiple myeloma to date. The pri­mary end­point of the trial was PFS. Data for over­all survival, the key sec­ond­ary end­point of the trial, are not yet mature. Other sec­ond­ary end­points in­clude over­all response rate, duration of response and safety[12]. 

About Farydak®

Panobinostat is approved as Farydak® in the US and Chile in com­bi­na­tion with bor­tez­o­mib and dex­a­meth­a­sone for the treat­ment of patients with multiple myeloma who have received at least two prior regi­mens, in­clud­ing bor­tez­o­mib and an IMiD[7]. Farydak, an HDAC inhibitor, has an impact on epigenetics and may help restore cell function in patients with multiple myeloma.

Additional regu­la­tory sub­missions for Farydak are being reviewed by health author­i­ties world­wide. The safety and efficacy profile of panobinostat has not yet been estab­lish­ed outside the approved indi­ca­tions. Because of the uncertainty of clin­i­cal trials, there is no guar­an­tee that panobinostat will become commercially avail­able for addi­tional indi­ca­tions any­where else in the world.

Disclaimer

The foregoing release con­tains forward-looking state­ments that can be identified by words such as "rec­ommended," "would," "positive opinion," "will," "recommendation," "may," "being reviewed," "yet," or similar terms, or by express or implied discussions regarding poten­tial future market­ing approvals for Farydak, or regarding poten­tial future revenues from Farydak. You should not place undue reliance on these state­ments. Such forward-looking state­ments are based on the current beliefs and ex­pec­ta­tions of man­age­ment regarding future events, and are subject to sig­nif­i­cant known and unknown risks and un­cer­tain­ties. Should one or more of these risks or un­cer­tain­ties materialize, or should under­lying assump­tions prove incorrect, actual results may vary materially from those set forth in the forward-looking state­ments. There can be no guar­an­tee that Farydak will be approved for sale in any market where it has been submitted, or at any particular time.  Neither can there be any guar­an­tee that Farydak will be submitted or approved for any addi­tional indi­ca­tions or labeling in any market, or at any particular time. Nor can there be any guar­an­tee that Farydak will be commercially successful in the future. Continued approval of Farydak in the approved indi­ca­tion may be contingent upon veri­fi­ca­tion and description of clin­i­cal benefit in con­firmatory trials. In particular, man­age­ment's ex­pec­ta­tions regarding Farydak could be affected by, among other things, unexpected regu­la­tory actions or delays or gov­ern­ment reg­u­la­tion generally; the un­cer­tain­ties in­her­ent in research and devel­op­ment, in­­clud­ing unexpected clin­i­cal trial results and addi­tional analysis of existing clin­i­cal data; the com­pany's ability to obtain or maintain pro­pri­e­tary intellectual property protection; general economic and industry con­di­tions; global trends to­ward health care cost con­tainment, in­­clud­ing ongoing pricing pressures; unexpected manu­fac­tur­ing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Com­mis­sion. Novartis is providing the in­­for­ma­tion in this press release as of this date and does not under­take any obli­ga­tion to update any forward-looking state­ments con­tained in this press release as a result of new in­­for­ma­tion, future events or other­wise.

About Novartis

Novartis provides inno­va­tive health­care solu­tions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a di­vers­i­fied portfolio to best meet these needs: inno­va­tive medicines, eye care and cost-saving generic pharma­ceu­ticals. Novartis is the only global com­pany with leading positions in these areas. In 2014, the Group achieved net sales of USD 58.0 billion, while R&D throughout the Group amounted to approx­i­mately USD 9.9 billion (USD 9.6 billion excluding im­pair­ment and amortization charges). Novartis Group com­pa­nies employ approx­i­mately 120,000 full-time-equivalent asso­ci­ates. Novartis prod­ucts are avail­able in more than 180 countries around the world. For more in­­for­ma­tion, please visit http://www.novartis.com.

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[*]Trade name Velcade^® registered to Millennium Pharma­ceu­ticals, Inc.

References

[1] CHMP LBH589 Summary of Opinion.

[2] Grønbæk K, Treppendahl M, Asmarand F, Guldberg P. Epigenetic Changes in Cancer as Potential Targets for Prophylaxis and Maintenance Therapy. Basic & Clinical Pharmacology & Toxicology. 2008;103:389-396.

[3] Maes K, et al. Epigenetic Modulating Agents as a New Therapeutic Approach in Multiple Myeloma. Cancers. 2013;5:430-461.

[4] American Cancer Society. Multiple Myeloma. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf. Accessed June 2015.

[5] Myeloma Patients Europe. A Report on Myeloma Patient Perspectives. 2013. Available at http://www.mpeurope.org/publications/reports-and-position-statements/. Accessed June 2015.

[6] Novartis data on file.

[7] US Full Prescribing Information.

[8] The Leukemia and Lymphoma Society. Myeloma. Revised 2013;1:48.

[9] National Cancer Institute. A Snapshot of Multiple Myeloma. Available at: http://www.cancer.gov/researchandfunding/snapshots/myeloma. Accessed June 2015.

[10] Richardson P, Mitsiades C, Schlossman R, et al. The Treatment of Relapsed and Refractory Multiple Myeloma. Hematology. 2007;317-323.

[11] National Cancer Institute. SEER Stat Fact Sheets: Myeloma. Available at: http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed June 2015.

[12] San-Miguel J, et al. Randomized Phase 3 Trial of Panobinostat Plus Bortezomib and Dexamethasone Versus Placebo Plus Bortezomib and Dexamethasone in Relapsed or Relapsed and Refractory Multiple Myeloma. The Lancet Oncology. 2014.

Source: Novartis.