Novartis drug Odomzo® gains EU approval for locally advanced basal cell carcinoma, providing new non-invasive therapy for patients

• Approval follows positive CHMP opinion based on pivotal Phase II study showing durable objective response rate per central review of 56% in patients with laBCC[1]
   
• Basal cell carcinoma is the most common form of skin cancer and can be highly disfiguring and invasive at advanced stages[2]
   
• Odomzo (sonidegib), a smoothened inhibitor, is already approved in the US, Australia and Switzerland, with additional regulatory filings underway worldwide

Basel, August 20, 2015 - Novartis announced today that the European Commission has approved Odomzo^® (sonidegib, formerly LDE225) 200 mg capsules for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) who are not amenable to curative surgery or radiation therapy[1].

"I have seen first-hand the devastating impact advanced basal cell carcinoma can have on those living with the disease. As the lesions are usually highly visible and located predominantly on the face, they can impact patients both physically and emotionally," said Reinhard Dummer, MD, Professor and Vice Chairman, Department of Dermatology at the University of Zurich. "The approval of Odomzo brings new hope in the form of a non-invasive option to help treat this disfiguring and potentially life-threatening disease."

Basal cell carcinoma (BCC) consists of abnormal, uncontrolled growths or lesions that arise in the skin's basal cells, which line the deepest layer of the epidermis (the outermost layer of the skin)[3] and accounts for more than 80% of non-melanoma skin cancers[4]. Advanced BCC is thought to represent roughly 1-10% of all cases of BCC[5]-[7]. Although BCC rarely becomes advanced, there have been few treatment options at this stage of the disease. Worldwide incidence of BCC is rising by 10% each year due to factors such as an aging population and increased ultraviolet exposure[8].

The EU approval of Odomzo was based on data from the Phase II randomized, double-blind, multi-center BOLT (Basal cell carcinoma Outcomes in LDE225 Trial) study in patients with laBCC not amenable to local therapy or metastatic basal cell carcinoma (mBCC). In patients with laBCC treated with Odomzo 200 mg, the objective response rate (ORR) was 56% per central review and 71% per investigator review. The median duration of response per central review has not been reached. The median progression-free survival was 22 months per central review and 19 months per investigator review. The most frequent grade 3 and 4 adverse reactions occurring in at least 2% of patients treated with Odomzo 200 mg were fatigue, decreased weight and muscle spasms[1].

"We are pleased to have a new treatment option for European patients living with advanced basal cell carcinoma," said Bruno Strigini, President, Novartis Oncology. "This milestone follows the recent approval of Odomzo in the US and is the latest example of our commitment to precision oncology and developing targeted treatments to address unmet needs."

The EU approval follows a positive opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) in June 2015 and applies to all 28 EU member states, plus Iceland, Norway and Liechtenstein. Outside the EU, Odomzo is approved in the United States, Australia and Switzerland. Additional regulatory submissions are being reviewed by health authorities worldwide.

About the BOLT Clinical Trial
The primary endpoint of the BOLT study was ORR of patients treated with Odomzo 200 mg and 800 mg, defined as the proportion of patients with confirmed complete or partial tumor response, or shrinkage, as measured by a central review committee. There was no evidence of better ORR among patients with laBCC randomized to receive Odomzo 800 mg daily. The secondary endpoints included duration of response, time to tumor response and progression-free survival as determined by central review[1].

Patients with laBCC treated with Odomzo 200 mg (n=66) were followed for at least 18 months unless discontinued earlier. The ORR per central review of 56% (95% confidence interval: 43, 68) consisted of 5% (n=3) complete responses (CR), or 23% using a pre-specified CR assessment similar to other laBCC trials, and 52% (n=34) partial responses (PR). The 71% ORR (95% confidence interval: 59, 82) per investigator review consisted of 9% (n=6) CR and 62% (n=41) PR[1].

The evaluation of tumor response was based on a composite assessment of modified Response Evaluation Criteria in Solid Tumors (mRECIST) that integrated tumor measurements obtained by radiographic assessments of target lesions (per RECIST 1.1), digital clinical photography (World Health Organization (WHO) adapted criteria) and histopathology assessments (via punch biopsies). All modalities used must have demonstrated absence of tumor to achieve a composite assessment of CR[1].

The most serious risks of Odomzo are embryofetal toxicity and musculoskeletal adverse reactions including rhabdomyolysis. Musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase (CK) elevations, may occur with Odomzo and other drugs that inhibit the hedgehog pathway. The incidence of musculoskeletal adverse reactions in patients with laBCC treated with Odomzo 200 mg was 54%, with 8% reported as grade 3 or 4. Adverse reactions occurring in more than 10% of patients treated with Odomzo 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting and pruritus. The most frequent grade 3 and 4 adverse reactions occurring in at least 2% of patients treated with Odomzo 200 mg were fatigue, decreased weight and muscle spasms[1].

About Odomzo
Odomzo (sonidegib, formerly LDE225) is an oral, selective smoothened (SMO) inhibitor approved by the European Commission for the treatment of adult patients with laBCC who are not amenable to curative surgery or radiation therapy[1]. SMO is a molecule that regulates the hedgehog (Hh) signaling pathway, which plays a critical role in stem cell maintenance and tissue repair, as well as in advanced basal cell carcinoma[9]-[11]. Odomzo is currently in clinical development in other diseases.

Outside of the European Union, Odomzo is approved in the United Sates for laBCC that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy; in Australia for the treatment of laBCC that is not amenable to curative surgery or radiation therapy, or for those with mBCC; and in Switzerland for the treatment of advanced BCC that is not amenable to curative surgery or radiotherapy. Additional regulatory submissions are being reviewed by health authorities worldwide.

IMPORTANT SAFETY INFORMATION
Important note: please see the locally approved full prescribing information.

Odomzo is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) who are not amenable to curative surgery or radiation therapy. Dosage and administration for adults is one 200 mg dose taken orally once daily on an empty stomach, at the same time each day. 

Odomzo is contraindicated in women who are pregnant or breast-feeding.

Creatine phosphokinase (CK) levels should be checked prior to starting treatment and as clinically indicated thereafter, for example, if muscle related symptoms are reported. If clinically notable elevation of CK is detected, renal function should be assessed. Dose modification or interruption guidelines should be followed. Patients should be closely monitored for muscle related symptoms if Odomzo is used in combination with certain medications that may increase the potential risk of developing muscle toxicity. Doctors should closely monitor patients with neuromuscular disorders due to an increased risk of muscle toxicity.

Patients should be instructed not to donate blood while taking Odomzo and for at least 20 months after ending treatment.

Women of childbearing potential must use highly effective contraception while receiving Odomzo. Contraception must be continued for 20 months after ending treatment. Negative pregnancy status must be confirmed by a test performed by a healthcare provider prior to initiation of Odomzo treatment. Odomzo must not be used during pregnancy. Women must not breast feed while taking Odomzo and for at least 20 months after ending treatment.

Men should not father a child or donate semen while taking Odomzo and for at least 6 months after ending treatment. Sexually active males must use a condom, regardless of vasectomy status, during intercourse and for at least 6 months after ending treatment.

Male and female fertility may be compromised with Odomzo. Fertility preservation strategies should be discussed prior to starting treatment with Odomzo.

Odomzo can cause side effects. Very common (>=10%) adverse drug reactions include amenorrhea, decreased appetite, dysgeusia, headache, nausea, diarrhea, vomiting, abdominal pain, alopecia, pruritus, muscle spasms, myalgia, musculoskeletal pain, fatigue, pain, and weight loss. Common (between 1 to 10%) adverse drug reactions include constipation, dyspepsia, gastroesophageal reflux disorder, rash, abnormal hair growth, myopathy (muscular fatigue and muscular weakness), and dehydration.

Very common laboratory abnormalities include decreased hemoglobin, decreased lymphocyte count, increased amylase, increased blood glucose, increased lipase, increased serum creatine phosphokinase, increased serum creatinine, increased alanine amino transaminase (ALT), and increased aspartate amino transaminase (AST).

Concomitant use of strong CYP3A inhibitors and inducers must be avoided. If a strong CYP3A inducer must be used concomitantly with Odomzo, consideration should be given to increasing the dose of Odomzo by 200 mg increments to a maximum daily dose of 800 mg.

Doctors should carefully monitor patients for adverse drug reactions with concomitant use of substrates of CYP2B6 and CYP2C9 enzymes or BCRP transporter, especially those with a narrow therapeutic range.

Due to overlapping toxicities, patients taking Odomzo who are also taking medications known to increase the risk of muscle-related toxicity may be at increased risk of developing muscle-related adverse events. Patients should be closely monitored and dose adjustments should be considered if muscle symptoms develop.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "positive opinion," "underway," "hope," "rising," "commitment," "being reviewed" or similar terms, or by express or implied discussions regarding potential new indications or labeling for Odomzo, or regarding potential future revenues from Odomzo. 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 Odomzo 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 Odomzo will be commercially successful in the future. In particular, management's expectations regarding Odomzo 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 safety issues; 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 150 countries around the world. For more information, please visit http://www.novartis.com.

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References
[1] Odomzo^® (sonidegib) Summary of Product Characteristics. Basel, Switzerland: Novartis Pharma AG; August 2015.
[2] Skin Cancer Foundation. "Skin Cancer Facts." Available at: http://www.skincancer.org/skin-cancer-information/skin-cancer-facts#general. Accessed on July 22, 2015.
[3] Skin Cancer Foundation. "Basal Cell Carcinoma." Available at: http://www.skincancer.org/skin-cancer-information/basal-cell-carcinoma. Accessed on July 22, 2015.
[4] Cleveland Clinic. "Nonmelanoma Skin Cancer." Available at: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/dermatology/nonmelanoma-skin-cancer/. Accessed on July 22, 2015.
[5] Danial C, Lingala B, Balise R, Oro AE, Reddy S, Colevas A, Chang AL. Markedly improved overall survival in 10 consecutive metastatic basal cell carcinoma patients. Br J Dermatol 2013: 1365-2133.
[6] Soleymani AD, Scheinfeld N, Vasil K, Bechtel MA. Metastatic basal cell carcinoma presenting with unilateral upper extremity edema and lymphatic spread. J Am Acad Dermatol. 2008;59(2 suppl 1):s1-s3.
[7] Moser S, Borm J, Mihic-Probst D, Jacobsen C, Kruse Gujer AL. Metastatic basal cell carcinoma: report of a case and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013.
[8] Wong C S M, Strange R C, Lear J T. Basal cell carcinoma. BMJ. 2003; 327:794-798.
[9] Stuetz A, et al. LDE225, a specific smoothened inhibitor, for the topical treatment of nevoid basal cell carcinoma syndrome (Gorlin's syndrome). Melanoma Research. 2010;20:e40.
[10] Gupta S, Takebe N, LoRusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol. 2010 July; 2(4): 237-250.
[11] Lin TL, Matsui W. Hedgehog pathway as a drug target: Smoothened inhibitors in development. Onco Targets Ther. 2012; 5:47-58.

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