• Results show statistically significant and clinically relevant increase in median progression-free survival with LBH589 plus bortezomib and dexamethasone[1]
• LBH589, a first-in-class treatment for patients with relapsed/refractory multiple myeloma if approved, helps extend benefit of standard-of-care therapy[1]
• First Phase III study to demonstrate superiority of a three-drug over two-drug combination in this patient population[1]
• Multiple myeloma, the second most common blood cancer, is incurable; most patients will relapse or become refractory so new treatments are needed[2],[3]

Basel, Switzerland (Press Release) - Data published today in The Lancet Oncology dem­onstrated a statistically sig­nif­i­cant and clin­i­cally relevant 4-month im­prove­ment in median pro­gres­sion-free survival (PFS) (hazard ratio=0.63 [95% con­fi­dence in­ter­val (CI): 0.52 to 0.76]; p<0.0001) for patients with re­lapsed or re­lapsed and refractory multiple myeloma when using the inves­ti­ga­tional com­­pound LBH589 (panobinostat) in com­bi­na­tion with bor­tez­o­mib* and dexa­meth­a­sone compared to placebo plus the same com­bi­na­tion[1]. In the Phase III PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) trial, the addi­tion of LBH589 also led to clin­i­cally meaningful in­­creases in com­plete and near com­plete response rates and duration of response. The effect of LBH589 was observed across all patient subgroups[1].

Multiple myeloma is a cancer of white blood cells that predominantly affects the bone marrow, impacting approx­i­mately 1 to 5 in every 100,000 people world­wide each year, and is in­creas­ing in prevelance[4],[5]. Most people with multiple myeloma ultimately relapse and become resistant to treat­ment, so new ther­a­pies with novel mech­a­nisms of action are critical for continuing to man­age the disease and im­prove out­comes[3]. If approved, LBH589, a pan-deacetylase (pan-DAC) inhibitor, will be first in its class of anticancer agents avail­able to this pop­u­la­tion[1].

"The PANORAMA-1 study is the first Phase III trial to show the superiority of LBH589 plus bor­tez­o­mib and dexa­meth­a­sone over one of the standard two-drug regi­mens for patients with relapsing and/or refractory multiple myeloma," said lead study investigator Jesus San-Miguel, MD, Director of Clinical and Translational Medicine, Clínica Universidad de Navarra, Pamplona, Spain. "These results show that by adding a new mech­a­nism of action, pan-DAC inhibition, there is a sig­nif­i­cant benefit for this patient pop­u­la­tion."

Side effects were con­sis­tent with those pre­vi­ously seen in LBH589 studies. The most common Grade 3/4 adverse events in the LBH589 com­bi­na­tion arm were thrombo­cytopenia (67% versus 31% with placebo), lymphopenia (53% versus 40% with placebo), neu­tro­penia (35% versus 11% with placebo), diarrhea (26% versus 8% with placebo) and neu­rop­athy (18% versus 15% with placebo)[1]. Adverse events were generally man­ageable through sup­port­ive care and dose reductions[1].

"The majority of people living with multiple myeloma eventually will stop responding to treat­ment or relapse, which underscores the need for new treat­ment options," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "The PANORAMA-1 results provide strong evi­dence of the poten­tial impact LBH589 could have for the multiple myeloma com­munity. We are committed to work­ing with regu­la­tory author­i­ties to make this treat­ment avail­able to patients as soon as possible."

Based on the PANORAMA-1 data, in May, LBH589 was granted priority review by the US Food and Drug Admin­istra­tion (FDA) and a regu­la­tory appli­ca­tion was submitted to the European Medicines Agency (EMA). Additional global regu­la­tory sub­missions are underway. FDA priority review status is given to ther­a­pies that may offer major ad­vances in treat­ment[6].

About PANORAMA-1

The PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) clin­i­cal trial is a Phase III ran­dom­ized, double-blind, placebo-controlled, multi­center global registration trial to eval­u­ate LBH589 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. The pri­mary end­point of the trial was pro­gres­sion-free survival (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[1].

About LBH589 and its epigenetic role in multiple myeloma

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[7]. Multiple myeloma is an incurable disease with a high rate of relapse (when the cancer returns) and resistance (when the ther­apy stops work­ing), despite cur­rently avail­able treat­ments[8]. It typically occurs in individuals 60 years of age or older, with few cases in individuals younger than 40[5].

Epigenetics is the cell pro­gramming that governs gene ex­pres­sion and cell devel­op­ment[9]. In multiple myeloma, the normal epigenetic process is disrupted (also called epigenetic dysregulation) resulting in the growth of can­cer­ous plasma cells, poten­tial resistance to current treat­ment and ultimately disease pro­gres­sion[10],[11].

LBH589 is a potent pan-DAC inhibitor that if approved will be a first-in-class treat­ment for patients with re­lapsed or re­lapsed and refractory multiple myeloma[12]. As an epigenetic regulator, LBH589 may help restore cell pro­gramming in multiple myeloma[13].

Because LBH589 is an inves­ti­ga­tional com­­pound, the safety and efficacy profile has not yet been estab­lish­ed. Access to this inves­ti­ga­tional com­­pound is avail­able only through carefully controlled and monitored clin­i­cal trials. These trials are designed to better under­stand the poten­tial benefits and risks of the com­­pound. Because of the uncertainty of clin­i­cal trials, there is no guar­an­tee that LBH589 will ever be commercially avail­able any­where in the world.

Disclaimer

The foregoing release con­tains forward-looking state­ments that can be identified by words such as "offers," "will," "investigational," "increasing," "ultimately," "potential," "committed," "priority review," "underway," "may," "offer," "yet," or similar terms, or by express or implied discussions regarding poten­tial market­ing approvals for LBH589, or regarding poten­tial future revenues from LBH589. 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 LBH589 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 LBH589 will be submitted or approved for sale in any addi­tional markets, or at any particular time. Nor can there be any guar­an­tee that LBH589 will be commercially successful in the future. In particular, man­agement's ex­pec­ta­tions regarding LBH589 could be affected by, among other things, the un­cer­tain­ties in­her­ent in research and devel­op­ment, in­­clud­ing unexpected clin­i­cal trial results and addi­tional analysis of existing clin­i­cal data; unexpected regu­la­tory actions or delays or gov­ern­ment reg­u­la­tion generally; 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, cost-saving generic pharma­ceu­ticals, preventive vaccines, over-the-counter and animal health prod­ucts. Novartis is the only global com­pany with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 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 135,000 full-time-equivalent asso­ci­ates and sell prod­ucts in more than 150 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] 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.
[2] National Cancer Institute. A Snapshot of Multiple Myeloma. Available at: http://www.cancer.gov/researchandfunding/snapshots/myeloma. Accessed July 2014.
[3] Richardson P, Mitsiades C, Schlossman R, et al. The Treatment of Relapsed and Refractory Multiple Myeloma. Hematology. 2007;317-323.
[4] Parkin M, et al. Global Cancer Statistics, 2002. CA Cancer J Clin. 2005;55:74-108.
[5] National Cancer Institute. SEER Stat Fact Sheets: Myeloma. Available at: http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed July 2014.
[6] US Food and Drug Admin­istra­tion. For Consumers. Available at: http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm#priorityreview. Accessed July 2014.
[7] American Cancer Society. Multiple Myeloma. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf. Accessed July 2014.
[8] The Leukemia and Lymphoma Society. Myeloma. Revised 2013;1:48.
[9] 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.
[10] Smith EM, Boyd K, Davies FE. The Potential Role of Epigenetic Therapy in Multiple Myeloma. Br J Haematol. 2009;148:702-713.
[11] Muntean AG, Hess JL. Epigenetic Dysregulation in Cancer. Am J Pathol. 2009;175:1353-1361.
[12] Richardson P, et al. Panorama-1: A Randomized, Double-blind, Phase 3 Study of Panobinostat or Placebo plus Bortezomib and Dexamethasone in Relapsed or Relapsed and Refractory Multiple Myeloma. Abstract #8510. 50th American Society of Clinical Oncology (ASCO) 2014 Chicago, IL.
[13] Maes K, et al. Epigenetic Modulating Agents as a New Therapeutic Approach in Multiple Myeloma. Cancers. 2013;5:430-461

Source: Novartis.