Novartis drug Afinitor DISPERZ® receives FDA approval to treat TSC-associated partial-onset seizures

EAST HANOVER, N.J., April 10, 2018 /PRNewswire/ -- Novartis today announced that the US Food and Drug Administration (FDA) has approved Afinitor DISPERZ^® (everolimus tablets for oral suspension), for the adjunctive treatment of adult and pediatric patients aged two years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures. Afinitor DISPERZ is now the first approved pharmacologic therapy in the US specifically indicated for the treatment of this condition².

TSC is a rare genetic disorder affecting up to one million people worldwide³. Approximately 85% of individuals with TSC are affected by epilepsy, and uncontrolled seizures associated with TSC can be debilitating for patients¹. More than 60% of TSC patients who experience seizures stop responding to available anti-epileptic therapies¹. EXIST-3 is the first Phase III study to demonstrate the significant benefit of adjunctive Afinitor DISPERZ in the treatment of patients with TSC-associated partial-onset seizures⁴. Furthermore, Afinitor^® is the only approved non-surgical option indicated for treating TSC-associated non-cancerous brain tumors (subependymal giant cell astrocytoma, or SEGA) and TSC-associated kidney tumors (renal angiomyolipoma).

"We are pleased that this latest approval for Afinitor DISPERZ in the US will make an important difference to patients with tuberous sclerosis complex who experience partial-onset seizures, one of the most debilitating manifestations of TSC," said Ameet Mallik, Executive Vice President, Novartis Oncology US. "This is a welcome advance that reinforces the commitment of Novartis to patients with rare diseases."

The FDA approval of Afinitor DISPERZ was based on efficacy and safety data from a pivotal Phase III study, EXIST-3 (EXamining everolimus In a Study of TSC), which found that when used as an adjunctive therapy, Afinitor DISPERZ significantly reduced the frequency of treatment-resistant seizures associated with TSC compared to placebo. The median percentage reduction from baseline in seizure frequency was significantly greater among patients randomized to Afinitor DISPERZ low exposure (LE; 29.3%, 95% CI 18.8, 41.9; p=0.003) and high exposure (HE; 39.6%, 95% CI 35.0, 48.7; p<0.001) vs placebo (14.9%, 95% CI 0.1, 21.7). Seizure response rate (≥50% reduction) was also greater with Afinitor LE (28.2%, 95% confidence interval [CI] 20.3, 37.3) and HE (40.0%, 95% CI 31.5, 49.0; p<0.001) vs placebo (15.1%, 95% CI 9.2, 22.8). The most common all-grade adverse events of any cause reported during the core phase at frequencies > 15% in the Afinitor DISPERZ LE/HE arms included stomatitis, diarrhea, nasopharyngitis, upper respiratory tract infection, and pyrexia⁴.

Afinitor works by inhibiting the mammalian target of rapamycin (mTOR), a protein that regulates multiple cellular functions⁵. In TSC, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body as well as seizures and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in prolonged survival, seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death².

About EXIST-3 (EXamining everolimus In a Study of TSC) (NCT01713946)⁴
EXIST-3 is a Phase III, three-arm, randomized, double-blind, placebo-controlled study of the efficacy and safety of low and high exposure ranges of Afinitor DISPERZ as adjunctive therapy in patients with treatment-resistant TSC-associated partial-onset seizures, defined as inadequate control of partial-onset seizures despite the use of two or more sequential regimens of single or combined anti-epileptic drugs (AEDs). The study enrolled male and female participants (ages 2.2 – 56.3 years) who had a diagnosis of TSC per the modified Gomez criteria and experienced ≥ 16 partial-onset seizures during the baseline phase while receiving a stable dose of 1 to 3 concomitant AEDs.

The major efficacy outcome measure was the percentage reduction in seizure frequency from the Baseline phase, during the maintenance period of the core phase. Additional efficacy outcome measures included response rate, defined as at least a 50% reduction in seizure frequency from the baseline phase during the maintenance period of the core phase, and seizure freedom rate during the maintenance period of the core phase².

Efficacy and safety of two trough exposure concentrations of Afinitor DISPERZ, 3–7 ng/mL (LE) and 9–15 ng/mL (HE) were assessed. Patients in all treatment arms concomitantly received one to three AEDs during the eighteen weeks of study core phase. The youngest patient enrolled was two years of age.

The median number of seizures per week at baseline vs end of core phase was 8.6 vs 6.8 (LE); 9.5 vs 4.9 (HE) and 10.5 vs 8.5 (placebo).The median percentage reduction from baseline in seizure frequency was significantly greater among patients randomized to Afinitor DISPERZ LE (29.3%, 95% CI 18.8, 41.9; p=0.003) and HE (39.6%, 95% CI 35.0, 48.7; p<0.001) vs placebo (14.9%, 95% CI 0.1, 21.7). Seizure response rate (≥50% reduction) was also greater with Afinitor LE (28.2%, 95% confidence interval [CI] 20.3, 37.3) and HE (40.0%, 95% CI 31.5, 49.0) vs placebo (15.1%, 95% CI 9.2 – 22.8)³. A 25% or greater reduction in seizure frequency was observed in 61 LE patients (52.1%, 95% CI 42.7, 61.5) and 91 HE patients (70%, 95% CI 61.3, 77.7) vs 45 placebo patients (37.8%, 95% CI 29.1, 47.2). The seizure-free rate was 5.1% LE (95% CI 1.9, 10.8) and 3.8% HE (95% CI 1.3, 8.7) vs 0.8% placebo (95% CI 0, 4.6).

The most frequent (≥10%) all grade adverse events (AEs), of any cause, reported with Afinitor LE/HE vs placebo included stomatitis (54.7%/63.8% vs 9.2%), diarrhea (17.1%/21.5% vs 5.0%), nasopharyngitis (13.7%/16.2% vs 16.0%), upper respiratory tract infection (12.8%/15.4% vs 12.6%), pyrexia (fever) (19.7%/13.8% vs 5.0%), vomiting (12.0%/10.0% vs 9.2%), cough (11.1%/10.0% vs 3.4%), and rash (6.0%/10.0% vs 2.5%). Grade 3 or 4 AEs occurred in 21 (17.9%) patients in the LE group, 31 (23.8%) patients in the HE group and 13 (10.9%) patients in the placebo group³. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) in the LE/HE groups were stomatitis (3%/4%); pneumonia (1%/2% in HE group), and irregular menstruation (2% HE only). The most common key laboratory abnormality (incidence ≥ 50%) was hypercholesterolemia. The most common Grade 3-4 key laboratory abnormality (incidence ≥ 2%) was neutropenia.

About tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is a multi-organ disease with widely variable expression¹. It may cause non-cancerous tumors to form in vital organs including the brain, kidney, heart, lungs, and skin, as well as resulting disorders such as epilepsy, autism, cognitive impairment, behavioral problems, and psychiatric disorders. Many people with TSC show evidence of the disease in the first year of life. However, because manifestations vary from person to person and can take years to develop, many children are not diagnosed until later in life, often with the onset of seizures, skin lesions or other significant symptoms, such as developmental delays⁶. Because TSC is a lifelong condition, the latest professional diagnostic guidelines issued in 2012 advise that individuals be monitored by a doctor experienced with the disorder to ensure that tumor growth or new symptoms are identified early⁷.

About Afinitor (everolimus)
Afinitor (everolimus) (known as Votubia^® in some countries) is an oral inhibitor of the mTOR pathway. Afinitor DISPERZ is the first adjunctive treatment approved in the US specifically for adult and pediatric patients aged 2 years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures. The product is also approved in more than 30 countries, including EU member states, for the treatment of patients with TSC-associated seizures.

Afinitor/Votubia is also approved in more than 95 countries, including the US, EU member states and Japan, for treatment of certain patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated renal angiomyolipoma.

Afinitor is a kinase inhibitor indicated for the treatment of:

• Postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.
• Adults with progressive neuroendocrine tumors of pancreatic origin (PNET) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Limitation of Use: Afinitor is not indicated for the treatment of patients with functional carcinoid tumors.
• Adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.
• Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.
• Afinitor and Afinitor DISPERZ are kinase inhibitors indicated for the treatment of adult and pediatric patients aged 1 year and older with TSC who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.
• Afinitor DISPERZ is a kinase inhibitor indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

Everolimus, the active ingredient in Afinitor/Afinitor DISPERZ/Votubia, is available under the trade names Zortress^® and Certican^® for use in other non-oncology indications and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important safety information
Patients should not take Afinitor or Afinitor DISPERZ if they are allergic to Afinitor or AFINITOR DISPERZ or to any of its ingredients. Patients should tell their healthcare provider before taking Afinitor or Afinitor DISPERZ if they are allergic to sirolimus (Rapamune^®) or temsirolimus (Torisel^®). Afinitor or Afinitor DISPERZ can cause serious side effects, including lung or breathing problems, infections, and kidney failure, which can even lead to death. If patients experience these side effects, they may need to stop taking Afinitor or Afinitor DISPERZ for a while or use a lower dose. Patients should follow their healthcare provider's instructions.

In some patients, lung or breathing problems may be severe and can even lead to death. Patients should tell their healthcare provider right away if they have any of these symptoms: new or worsening cough, shortness of breath, chest pain, difficulty breathing, or wheezing.

Afinitor or Afinitor DISPERZ may make patients more likely to develop an infection, such as pneumonia, or a bacterial, fungal, or viral infection. Viral infections may include reactivation of hepatitis B in people who have had hepatitis B in the past. In some people these infections may be severe and can even lead to death. Patients may need to be treated as soon as possible. Patients should tell their healthcare provider right away if they have a temperature of 100.5˚F or above, chills, or do not feel well. Symptoms of hepatitis B or infection may include the following: fever, chills, skin rash, joint pain and inflammation, tiredness, loss of appetite, nausea, pale stools or dark urine, yellowing of the skin, or pain in the upper right side of the stomach.

Severe allergic reactions can happen in patients who take Afinitor or Afinitor DISPERZ.  Patients should contact their healthcare provider or get medical help right away if they get signs and symptoms of a severe allergic reaction including: rash, itching, hives, flushing, trouble breathing or swallowing, chest pain or dizziness.

Patients who take an angiotensin-converting enzyme (ACE) inhibitor medicine during treatment with Afinitor or Afinitor DISPERZ are at a possible increased risk for a type of allergic reaction called angioedema. Patients should talk with their healthcare provider before taking Afinitor or Afinitor DISPERZ if they are not sure if they take an ACE inhibitor medicine. Patients should get medical help right away if they have trouble breathing or develop swelling of the tongue, mouth, or throat during treatment with Afinitor or Afinitor DISPERZ.

Afinitor or Afinitor DISPERZ may cause kidney failure. In some people this may be severe and can even lead to death. Patients should have tests to check their kidney function before and during their treatment with Afinitor or Afinitor DISPERZ.

Afinitor can cause incisions to heal slowly or not heal well. Patients should tell their healthcare provider if their incision is red, warm, or painful; if they have blood, fluid, or pus in their incision; or if their incision opens up or is swollen.

Increased blood sugar and fat (cholesterol and triglycerides) levels in the blood may occur. A healthcare provider should perform blood tests to check the patient's fasting blood sugar, cholesterol and triglycerides levels in the blood before starting and during treatment with Afinitor or Afinitor DISPERZ.

Afinitor and Afinitor DISPERZ can cause decreased red blood cells, white blood cells, and platelets. The healthcare provider should do blood tests to check blood cell counts before the patient starts and during treatment with Afinitor or Afinitor DISPERZ.

Afinitor or Afinitor DISPERZ can cause harm to a patient's unborn baby. Patients should talk to their healthcare provider about birth control methods that may be right for them during this time.

Afinitor or Afinitor DISPERZ can cause mouth ulcers and sores. When a patient starts treatment with Afinitor, their healthcare provider may also prescribe a mouthwash to reduce the likelihood of getting mouth ulcers or sores and to reduce their severity. Other common side effects include: infections, rash, feeling weak or tired, diarrhea, swelling of arms, hands, feet, ankles, face or other parts of the body, stomach-area (abdominal) pain, nausea, fever, cough, headache, decreased appetite, respiratory tract infections, the absence of menstrual periods (menstruation), and may affect fertility in females and the ability to become pregnant, and fertility in males and the ability to father a child.

Please see full Prescribing Information for Afinitor and Afinitor DISPERZ available at www.Afinitor.com.

Rapamune^® (sirolimus) and Torisel^® (temsirolimus) are registered trademarks of Wyeth Pharmaceuticals Inc.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations 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 the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward healthcare cost containment, including government, payor and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, 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
Located in East Hanover, NJ Novartis Pharmaceuticals Corporation is an affiliate of Novartis which 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, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2017, the Group achieved net sales of USD 49.1 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 122,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

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References
1.  Chu-Shore CJ, et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010: 51(7): 1236-1241.
2.  Afinitor/Afinitor DISPERZ (everolimus) Prescribing information. East Hanover, New Jersey, USA: Novartis Pharmaceuticals Corporation; April 2018.
3.   ASCO CancerNet.com https://www.cancer.net/cancer-types/tuberous-sclerosis-complex. Accessed 6 Feb 2018.
4.   French JA, Lawson JA, Yapici Z et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016; 388: 2153-63.
5.   Wong M. Mammalian target of rapamycin (mTOR) pathways in neurological diseases. Biomed J. 2013; 36(2): 1-17.
6.   Budde K, Gaedeke J. Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition. American J of Kidney Diseases. 2012:276-283.
7.   Northrup H. et al. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012international tuberous sclerosis complex consensus conference. Pediatric Neurology. 2013; 49: 243-254.

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