Ligand Partner Lundbeck Receives FDA Approval of Carnexiv™ (carbamazepine) Injection as Intravenous Short-Term Replacement Therapy for Certain Seizure Types

Carnexiv is the first FDA-approved intravenous carbamazepine option

Ligand earns $1.25 million milestone payment to be recognized in the fourth quarter

SAN DIEGO--(BUSINESS WIRE)-- Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) partner Lundbeck announced today that the U.S. Food and Drug Administration (FDA) has approved Carnexiv™ (carbamazepine) injection as a short-term replacement therapy for oral carbamazepine formulations in adults with certain seizure types when oral administration is temporarily not feasible. Carnexiv received orphan drug designation for this indication and will be the first available intravenous (IV) formulation of the antiepileptic drug (AED) carbamazepine. Lundbeck plans to make Carnexiv commercially available in the United States in early 2017. With the approval, Ligand has earned a $1.25 million milestone payment. Ligand is also entitled to receive a royalty of 2.75% on net sales of Carnexiv.

Carnexiv is a short-term (≤7 days) intravenous replacement therapy for oral carbamazepine formulations that provides continuity of care for adult patients who are unable to take carbamazepine by mouth and have the following seizure types:

• Partial seizures with complex symptomatology
• Generalized tonic-clonic seizures
• Mixed seizure patterns which include the above, or other partial or generalized seizures

As with the oral carbamazepine formulation, there is a risk of serious dermatologic reactions during treatment with Carnexiv, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), as well as a risk of aplastic anemia and agranulocytosis.

Partial seizures and generalized tonic-clonic seizures can often be difficult to control.¹ As a result, many patients with epilepsy are on a daily regimen of one or more AEDs that has been carefully adjusted to obtain a therapeutic response. Switching or an abrupt discontinuation of AEDs can lead to seizure recurrence or breakthrough seizures.^2,3

Researchers at the University of Minnesota College of Pharmacy helped conduct early clinical proof-of-concept studies, which were instrumental in developing the formulation of Carnexiv, making intravenous administration possible. James Cloyd, PharmD, Angela Birnbaum, PhD and Ilo E. Leppik, MD at the University of Minnesota partnered closely with Lundbeck during the clinical trial and approval process for Carnexiv.

Ligand’s previous outlook for third quarter 2016 revenue was approximately one-third of the projected total revenues for the second half of 2016 of $66 million to $70 million. The Carnexiv approval milestone had been anticipated for the third quarter and now will be recognized in the fourth quarter.

About Carnexiv™ (carbamazepine) injection

Carnexiv is an intravenous antiepileptic drug developed in the United States by Lundbeck and approved for use in the United States. Carnexiv is a short-term (≤7 days) replacement therapy for oral carbamazepine for patients who are unable to take medication by mouth. When switching from oral carbamazepine, the total daily dosage of Carnexiv should be 70 percent of the total daily dose of oral carbamazepine, divided equally into four separate 30-minute infusions separated by 6 hours. At the end of the intravenous replacement period, patients should be switched back to their previous oral carbamazepine total daily dose and frequency as soon as clinically appropriate.

Indications and Usage

CARNEXIV (carbamazepine) injection is indicated as replacement therapy for oral carbamazepine formulations, when oral administration is temporarily not feasible, in adults with the following seizure types:

• Partial seizures with complex symptomatology
• Generalized tonic-clonic seizures
• Mixed seizure patterns which include the above, or other partial or generalized seizures

Limitations of Usage

CARNEXIV is not indicated for the treatment of absence seizures (including atypical absence). Carbamazepine has been associated with increased frequency of generalized convulsions in these patients.

Important Safety Information

WARNING: SERIOUS DERMATOLOGIC REACTIONS and APLASTIC ANEMIA AND AGRANULOCYTOSIS

See full prescribing information for complete boxed warning.

Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have occurred with carbamazepine. Discontinue CARNEXIV if these reactions occur Patients of Asian ancestry have a 10-fold greater risk of TEN/SJS, compared to other populations. Avoid use of CARNEXIV in genetically at-risk patients, including those positive for the HLA-B*1502 allele

Aplastic Anemia and Agranulocytosis

Aplastic anemia and agranulocytosis can occur with CARNEXIV Obtain complete CBC prior to initiation of CARNEXIV. Consider discontinuing CARNEXIV if significant bone marrow depression develops

Contraindications: Bone Marrow Depression, Hypersensitivity, and Concomitant Drugs

• Patients with bone marrow depression or a known hypersensitivity to carbamazepine or tricyclic antidepressants. If patient or immediate family member has history of hypersensitivity, consider benefits and risks and closely monitor for symptoms
• Concomitant use with boceprevir, nefazodone, and delavirdine or other non-nucleoside reverse transcriptase inhibitors
• Use of monoamine oxidase inhibitors (MAOIs) within the past 14 days before beginning carbamazepine treatment

Toxic Epidural Necrolysis (TEN), Stevens-Johnson syndrome (SJS), HLA-B*1502 Allele, and Aplastic Anemia and Agranulocytosis (see Boxed Warning)

Renal Impairment

CARNEXIV should generally not be used in patients with moderate or severe renal impairment. Closely monitor patients with renal impairment.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

DRESS, also known as multiorgan hypersensitivity, has occurred with carbamazepine. These events can be fatal or life-threatening. Advise patients to report signs and symptoms such as fever, rash, lymphadenopathy, and/or facial swelling immediately, and discontinue CARNEXIV if an alternative etiology cannot be established.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including CARNEXIV, increase the risk of suicidal thoughts or behavior. Monitor patients for the emergence or worsening of depression, any unusual changes in mood or behavior, or suicidal thoughts, behavior, or thoughts of self-harm; and instruct families and caregivers to report behaviors of concern immediately.

Pregnancy Registry and Nursing Mothers

• CARNEXIV can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant while taking CARNEXIV, inform the patient of the potential risk to the fetus and carefully consider both the potential risks and benefits of treatment. Encourage patients to call the toll-free number 1-888-233-2334 to enroll in the Pregnancy Registry or visit http://www.aedpregnancyregistry.org/.
• Discontinue CARNEXIV or discontinue nursing, taking into consideration the importance of the drug to the mother.

Abrupt Discontinuation and Seizure Risk

Do not discontinue CARNEXIV abruptly because of the risk of seizures, status epilepticus, and other withdrawal signs/symptoms.

Hyponatremia

Hyponatremia can result from treatment with CARNEXIV, and in many cases appears to be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The risk of SIADH appears to be dose-related. Elderly patients and patients treated with diuretics are at a greater risk. Consider discontinuing CARNEXIV in patients with symptomatic hyponatremia.

Neurologic Function

Carbamazepine has the potential to impair judgment, cognition, motor function, and motor coordination, and it may also cause dizziness, ataxia, and drowsiness. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that carbamazepine does not affect them adversely.

Hepatic Toxicity

Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure, have been reported, and may progress despite drug discontinuation. Rare instances of vanishing bile duct syndrome have also been reported. Evaluate liver function before and during treatment, particularly in patients with a history of liver disease. Discontinue CARNEXIV based on clinical judgment in the case of active liver disease, or with newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage. Avoid using CARNEXIV in patients with a history of hepatic porphyria.

Increased Intraocular Pressure

Carbamazepine has mild anticholinergic activity. Consider assessing intraocular pressure before initiating and periodically during therapy in patients with a history of increased intraocular pressure.

Hepatic Porphyria

Avoid using CARNEXIV in patients with a history of hepatic porphyria, as acute attacks have been reported in such patients and CARNEXIV increases porphyrin precursors in rodents.

Drug Interactions

Carbamazepine may reduce plasma concentrations of concomitant medications metabolized by CYP1A2, 2B6, 2C9/19 and 3A4; closely monitor carbamazepine levels and make appropriate dose adjustments. CYP3A4 inhibitors can increase plasma carbamazepine levels. CYP3A4 inducers can decrease carbamazepine levels.

Adverse Reactions

The most common adverse reactions with CARNEXIV (incidence ≥2%) were dizziness, somnolence, blurred vision, diplopia, headache, infusion-related reaction, infusion site pain, and anemia. The most common adverse reactions with oral carbamazepine were dizziness, drowsiness, unsteadiness, nausea, and vomiting.

Important Dosing Information

Use of CARNEXIV for more than 7 days has not been studied and is not recommended. At the end of intravenous (IV) replacement therapy, switch patients back to oral carbamazepine at their previous total daily oral dose and frequency as soon as clinically appropriate.

Please see the full Prescribing Information, including Boxed Warning for serious dermatologic reactions and aplastic anemia and agranulocytosis, for complete details; or go to www.CARNEXIV-US.com for more information.

CARNEXIV is a trademark of Lundbeck.
All other trademarks or registered trademarks are the property of their respective owners.

About Ligand Pharmaceuticals

Ligand is a biopharmaceutical company focused on developing or acquiring technologies that help pharmaceutical companies discover and develop medicines. Our business model creates value for stockholders by providing a diversified portfolio of biotech and pharmaceutical product revenue streams that are supported by an efficient and low corporate cost structure. Our goal is to offer investors an opportunity to participate in the promise of the biotech industry in a profitable, diversified and lower-risk business than a typical biotech company. Our business model is based on doing what we do best: drug discovery, early-stage drug development, product reformulation and partnering. We partner with other pharmaceutical companies to leverage what they do best (late-stage development, regulatory management and commercialization) to ultimately generate our revenue. Ligand’s Captisol^® platform technology is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. OmniAb^® is a patent-protected transgenic animal platform used in the discovery of fully human mono- and bispecific therapeutic antibodies. Ligand has established multiple alliances, licenses and other business relationships with the world's leading pharmaceutical companies including Novartis, Amgen, Merck, Pfizer, Celgene, Gilead, Janssen, Baxter International and Eli Lilly.

Follow Ligand on Twitter @Ligand_LGND.

Forward-Looking Statements

This news release contains forward-looking statements by Ligand that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. These include statements regarding Lundbeck’s plans to make Carnexiv commercially available in early 2017; Ligand’s future revenue; the timing of the $1.25 million payment payable to Ligand; the potential for Carnexiv to provide alternative treatment to AED carbamazepine; and the description of the side effects and commercial opportunity for Carnexiv. Actual events or results may differ from our expectations. For example, there can be no assurances that Lundbeck will successfully launch Carnexiv in 2017, if ever; the side effects or efficacy of Carnexiv may prove different or worse than the results from previous clinical trials; and Carnexiv may not be accepted as a treatment option by doctors and other health professionals. In addition, there can be no assurance that Lundbeck will make the required milestone payment. The failure to meet expectations with respect to any of the foregoing matters may reduce Ligand's stock price. Additional information concerning these and other important risk factors affecting Ligand can be found in Ligand's prior press releases available at www.ligand.com as well as in Ligand's public periodic filings with the Securities and Exchange Commission, available at www.sec.gov. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this press release, except as required by law. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

Sources

1. Mattson R, Cramer J, et al. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. N Engl J Med. 1992. 327(11):765-71.
2. Finamore JM, Sperling MR, et al. Seizure outcome after switching antiepileptic drugs: A matched, prospective study. Epilepsia. 2016 57(8):1294-300.
3. Wang SP, Mintzer ST, et al. Seizure recurrence and remission after switching antiepileptic drugs. Epilepsia 2013. 54:187-193

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Ligand Pharmaceuticals Incorporated
Todd Pettingill, 858-550-7500
investors@ligand.com
or
LHA
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Source: Ligand Pharmaceuticals Incorporated

Released October 7, 2016