Status: approved/marketed in U.S. and Europe

Organizations involved:

Merz GmbH & Co. KGaA – Manuf.; Leerink Swann analyst Seamus Fernandez said in a recent research note that Xeomin poses more of a threat to Medicis' Dysport than to Allergan's Botox. Heavy sampling has helped Merz land about 8% of the botulinium-toxin market, Fernandez wrote in a subsequent note. But, according to Xeomin's label, Merz's drug can iron out wrinkles for up to three months, while Botox's smoothing effects last up to four months. R&D; Tech.; Europe mark.

Allergan, Inc. – Patent dispute

Cross ref: See the entries above for Botulinum Toxin Products and Botulinum Toxin A (BOTOX).

Description: Xeomin is a lyophilized (freeze-dried) formulation of botulinum toxin type A free of complexing proteins manufactured by culture of Clostridium botulinum, Hall strain bacteria. The botulinum toxin complex is purified from the culture supernatant and then the active ingredient is chromatographically separated from the proteins (hemaglutinins and non-hemaglutinins) through a series of steps yielding the active neurotoxin without accessory proteins. The neurotoxin is a 150 kDa protein consisting of a heavy H chain (heavy chain, 100 kDa) and a light L chain (light chain, 50 kDa), linked by a disulfide bond. Accessory proteins are removed during the manufacturing process. Thus, unlike the botulinum toxin A in BOTOX and Dysport, the toxin of Xeomin is not complexed with hemagglutinin or any other protein; and is a botulinum toxin type A that is free from complexing proteins. This lack of complexed proteins may result in Xeomin being less immunogenic than competing botulinum toxin A products. The botulinum toxin type A complex (neurotoxin + accessory proteins) has a size of 900 kDa, of which 150 kDa is neurotoxin.

Xeomin is stabilized with Albumin, Human (human serum albumin; manufactured to European Pharmacopoeia specifications) and sucrose. Xeomin is packaged in type 1 borosilicate glass single-use vials with latex-free bromobutyl rubber closures and tamper-proof aluminum seals.

At least in the U.S., Xeomin is available in 50-unit and 100-unit vials, which Merz believes may allow for more precise billing and reduce wastage. Xeomin 100-unit vials each contain 100 mouse LD50 units of Clostridium botulinum toxin type A, corresponding to about 60 pg of clostridial protein. Xeomin is reconstituted prior to use with sterile, unpreserved normal saline solution (0.9% sodium chloride solution for injection). The shelf life is three years at room temperature. Reconstituted solution may be stored in the vial for up to 24 hours at 2-8°C (refrigerated).

The U.S. dating period for Xeomin is 36 months from the date of manufacture when stored at -20° C, 5° C and 25° C. Unopened vials of Xeomin can be stored at room temperature 20 to 25°C (68 to 77° F), in a refrigerator at 2 to 8°C (36 to 46°F), or a freezer at -20 to -10°C (-4 to 14°F) for up to 36 months. The date of manufacture shall be defined as the date of fina; [redacted/censored by FDA] of the formulated drug product. The dating period for the drug substance is 36 months from the date of manufacture when stored at -80 °C. Reconstituted Xeomin should be stored in a refrigerator at 2 to 8°C (36 to 46°F) and administered within 24 hours.

Xeomin is the only approved botulinum toxin that does not require refrigeration prior to reconstitution. Merz believes this may simplify product distribution and storage, and help ensure product integrity at the time of injection. Xeomin is the only botulinum neurotoxin that requires no refrigeration prior to reconstitution and can be stored at room temperature for up to 36 months. Xeomin is also the only type A botulinum neurotoxin that is available in 50-unit single use vials that may allow for a reduction in wastage and may minimize patient out-of-pocket expenses.

Biological.: Complexing of botulinum toxin A with hemagglutinin generally improves its stability, allowing parenteral/oral administration, e.g., botulism food poisoning from food containing complexes enzyme. The toxin-hemagglutinin complexes are hydrolyzed at physiological pH, allowing their direct injection into muscles.

Antigenicity studies have shown that pure uncomplexed botulinum neurotoxin of all types, in contrast to commercial products of type A and the complexes of types B to G, induces no, or at the most very little, formation of antibodies. In contrast to other products, no neutralizing antibodies could be detected in antigenicity studies with repeated intradermal administration of Xeomin in rabbits. However, Xeomin exhibits increased systemic toxicity compared to other products, resulting from its failure to induce neutralizing antibodies that usually diminish the clinical effect of botulinum neurotoxin type A; and, perhaps, associated with its lower molecular weight and ability to diffuse in tissues.

Preclinical studies conducted with Xeomin showed an acceptable safety profile and supported the use of Xeomin in an intramuscular administration regimen. Studies have shown that identical units of NT 201 and the complexed toxin in BOTOX were equally effective. In Xeomin clinical trials, individual dosages were based on the dosages of BOTOX received by patients in the two consecutive sessions prior to trial start.

Nomenclature: Botulinum Toxin A/Merz [BIO]; Xeomin [TR]; incobotulinumtoxinA [USAN INN]; Bocouture [TR For; in Germany, the United Kingdom, France, Italy and Spain]; Botulinum Toxin A [CAS]; 93384-43-1 [CAS RN]; Clostridium botulinum toxin type A [SY]; NT 201 [SY]; NDC 0259-1605-01 and NDC 0259-1610-01 [NDC]

Companies.: Xeomin, including the uncomplexed toxin, was developed by Merz GmbH & Co. KGaA (CBER/FDA est. no. 1830), which also manufactures the product in Dessau, Germany, and markets it in European countries.

FDA class: Biologic NDA

Approval: Date = 20100730; BLA 125360

Approval: Date = 20050531, approval in Germany (market authorization 57093.00.00)

Date = 20100802, sNDA; Indication = for the treatment of adults with cervical dystonia or blepharospasm. Date = 20110721, sNDA; Indication = for the temporary improvement in the appearance of moderate to severe glabellar lines, or frown lines between the eyebrows, in adult patients. Indications: [full text of the indications: and Usage section of the U.S. product insert/labeling; 7/2012]:

XEOMIN is an acetylcholine release inhibitor and neuromuscular blocking agent indicated for the:
• treatment of adults with cervical dystonia, to decrease the severity of abnormal head position and neck pain in both botulinum toxin-naïve and previously treated patients.
• treatment of blepharospasm in adults previously treated with onabotulinumtoxinA (Botox®).
• temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients.

[full text of the “Therapeutic indications:” section of the Merz English-language Summary of Product Characteristics (SPC), 5/2007]

Xeomin is indicated for the symptomatic management of blepharospasm and cervical dystonia of a predominantly rotational form (spasmodic torticollis) in adults.

Status: The BLA was filed in July 1, 2009 by Merz, and received standard review. Approval was granted on July 30, 2010. The FDA approval was based on the results of two pivotal U.S. clinical trials involving adult patients diagnosed with either cervical dystonia or blepharospasm. Additionally, active comparator studies conducted in Europe evaluating Xeomin versus Botox (onabotulinumtoxinA) were included among the data submitted in support of the registration filing in these conditions.

As part of the FDA approval, Merz was required to complete studies including: "submit safety data assessing distant spread of toxin effects after multiple administrations of Xeomin (incobotulinumtoxinA), during a minimum period of 12 months, collected in at least 100 pediatric patients (ages 2-17 years);" "submit safety data assessing distant spread of toxin effects after multiple administrations of Xeomin (incobotulinumtoxinA), during a minimum period of 12 months, collected in at least 100 adult patients;" a "randomized, double-blind, adequate and well controlled, multiple fixed-dose, parallel group clinical trial of Xeomin (incobotulinumtoxinA) in botulinum toxin-naive children age 2-17 years with lower extremity spasticity;" "randomized, double-blind, adequate and well controlled, multiple fixed-dose, parallel group clinical trial of Xeomin (incobotulinumtoxinA) in botulinum toxin-naive adults with lower extremity spasticity;" "randomized, double-blind, adequate and well controlled, multiple fixed-dose, parallel group clinical trial of Xeomin (incobotulinumtoxinA) in botulinum toxin-naive adults with upper extremity spasticity;" and "randomized, double-blind, adequate and well controlled, parallel group, clinical trial of Xeomin (incobotulinumtoxinA) in botulinum toxin-naive adults with blepharospasm." Merz also was required to file a Risk Evaluation and Mitigation Strategy (REMS) including development of a Medication Guide and "a [risks] communication plan."

Upon FDA approval, Merz reported, "More than 84,000 patients have been treated with Xeomin worldwide since 2005. The U.S. is the 20th country to approve Xeomin for the treatment of cervical dystonia and blepharospasm."     

In July 2007, EMEA, European Union, recommended approval of Xeomin, with full approval expected in several months. Approval was granted on Oct. 24, 2007.

In March 2012, in a U.S. District Court case brought by Allergan, the court ruled that Merz had poached and stolen marketing reps from Allergan and that these reps provided Merz with Allergan-proprietary information, leading the judge to temporarily halt Merz's planned U.s. launch of Xeomin for muscle spasms.

Xeomin had previously been approved and marketed in Germany, Denmark and Sweden.

Tech. transfer: Merz had filed EP1185291, “Therapeutic Agent Comprising a Botulinum Neurotoxin,” Allergan filed an opposition to this patent with the European Patent Office, and likely similarly challenged other Merz botulinum toxin A patents. This patent was revoked in April 2006, and Merz promptly filed an appeal, which is ongoing. First among the references cited is U.S. 5,512,547 assigned to the Wisconsin Alumni Research Fund (WARF; Univ. of Wisconsin; also discussed in the BOTOX entry), expiring on Oct 13, 2014, whose claim no. 1 states, “A pharmaceutical composition consisting essentially of: (a) isolated, essentially pure type A botulinum neurotoxin; (b) serum albumin; and (c) an effective amount of trehalose which stabilizes the neurotoxin and improves the shelf life of composition so that it is stable at temperatures up to about 37˚C,” with one or more examples of formulations containing albumin and sucrose as stabilizers (which together with the claims largely describes Xeomin).

In Oct. 2006, the U.K. High Court of Justice revoked Allergan’s botulinum toxin EP-B1 1 366 770 (in the U.K. only) after Merz, argued the patent lacked novelty and was obvious. Particularly cited were claim 1, “Use of the neurotoxin component of Botulinium toxin for the manufacture of a medicament for the treatment of pain associated with muscle activity or contracture,” and claim 5, “Use according to any one of the preceding claims, wherein the neurotoxin component of Botulinium type A, B, C, D, E, F or G.” EP-B1 1 366 770 was granted in 2005 by the European Patent Office for a variety of European member states, including Germany and Great Britain. This patent, applied for in 2003, was a second generation divisional patent, the original having been filed in 1994. By the revoked patent’s priority date, two formulations of botulinium toxins were commercially available (BOTOX and Dysport). Merz charged that the patent disclosed additional matter to that was not contained within the original application, since the original application referred only to the use of botulinium toxin to treat various disorders, while the specification of the later patent referred to the use of the neurotoxin component stripped of the NAPs (toxin A-binding proteins). Allergan argued that since the original application referred to the neurotoxin component in the technical background to the invention, the matter had been sufficiently disclosed, both explicitly and implicitly, by the original application. The presiding judge noted, “In this case, the skilled addressee would have viewed Claim 1 as covering use of the neurotoxic component regardless of whether it formed part of the toxin complex. Accordingly the original application disclosed only the use of the botulinum toxin - not the neurotoxic component stripped of the NAPs” [which would have covered Xeomin from Merz], and “the original application contained no explicit or implicit disclosure of the use of the neurotoxic component of the stripped botulinium toxin.” Allergan is appealing this ruling.

U.S. 7,879,341, "Therapeutic composition with a botulinum neurotoxin," assigned to Merz, expires July 19, 2025.' 7,964,199, "Therapeutic composition comprising a botulinum neurotoxin," assigned to Merz, expires in 2020. Botulinum toxin A-related EP patents assigned to Merz include: EP2048156, "Process for providing a temperature-stable muscle relaxant on the basis of the neurotoxic component of botulinum toxin," expiring in 2027; EP2305290, "Salt-free composition comprising an intact Botulinum toxin complex," expiring in 2029; EP2170375, "PROCESS FOR PROVIDING A TEMPERATURE - STABLE MUSCLE RELAXANT ON THE BASIS OF THE NEUROTOXIC COMPONENT OF BOTULINUM TOXIN IN SOLID FORM," expiring in 2028; and EP1786459, "THERAPEUTIC COMPOSITION WITh A BOTULINUM NEUROTOXIN," expiring 2025. Trials: More than 700 patients with blepharospasm or spasmodic torticollis (cervical dystonia of a predominantly rotational form) have been studied in Xeomin clinical trials. A total of five clinical trials have been completed in Europe and Israel. Two studies were conducted in 46 healthy volunteers. A further three studies in 816 patients were conducted to provide data on the safety and efficacy of Xeomin in the treatment of cervical dystonia (CD) and blepharospasm (BEB). Xeomin was shown to provide non-inferior efficacy and safety profiles in the treatment of CD and BEB compared with BOTOX. Xeomin showed a 1:1 toxin content ratio with BOTOX. Xeomin was effective, well tolerated and non-inferior to BOTOX in the treatment of both CD and BEB. There were no differences between the two therapies in terms of onset of action, duration and waning of effect.

Safety and effectiveness of Xeomin in children and adolescents (<18 years) have not been demonstrated.

Medical: The potency Units of XEOMIN (incobotulinumtoxinA) for injection are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of XEOMIN cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method.

Reconstituted Xeomin is intended for intramuscular injection. In Germany, Xeomin may only be used by physicians with suitable qualifications and proven experience in the application of Botulinum toxin and in the use of the necessary equipment, e.g. EMG. The optimum dosage and number of injection sites in the treated muscle is chosen by the physician individually for each patient. An injection volume of ~0.1 mL is recommended. A decrease or increase in the Xeomin dose is possible by administering a smaller or larger injection volume. The smaller the injection volume, the less pressure sensation and less spread of toxin, reducing effects on nearby muscles when small muscle groups are being injected.

The dosage scheme for Xeomin in the treatment of blepharospasm and cervical dystonia of a predominantly rotational form (spasmodic torticollis) is simple. The optimum dosage and number of injection sites in the treated muscle is individualized for each patient. A titration of the dose should be performed. For blepharospasm, the initial recommended dose is 1.25 - 2.5 units (0.05 - 0.1 ml solution) at each injection site. The maximum dose per injection site is 5 units; per treatment (bilateral) 100 units. The injections are given into the medial and lateral orbicularis oculi of the upper lid and the lateral orbicularis oculi of the lower lid. Additional sites in the brow area, the lateral orbicularis and in the upper facial area may also be injected if local spasms here interfere with vision. For spasmodic torticollis, the maximum dose per treatment is 300 units and 50 units per injection site. The sternocleidomastoid muscle should not be injected bilaterally as there is an increased risk of adverse effects (in particular dysphagia) when bilateral injections or doses in excess of 100 U are administered in this muscle. If difficulties arise in isolating the individual single muscles, the injections should be carried out with electromyographic (EMG) guidance. Merz provides recommended dosages for each of the relevant neck muscles.

Market: Xeomin was launched in the U.S. on Oct. 5, 2010.

On Jan. 4, 2012, the Centers for Medicare and Medicaid Services (CMS) assigned a product-specific Healthcare Common Procedure Coding System (HCPCS) billing code, J0588 "INJECTION, INCOBOTULINUMTOXIN A, 1 UNIT" for Xeomin, effective Jan. 1, 2012. Until individual government contractors, state Medicaid agencies and commercial payors update their systems to recognize the newly assigned J-Code, the Q-Code will continue to act as a product-specific reimbursement code for XEOMIN. In most circumstances, utilizing a product-specific Q-Code is administratively identical to billing under a permanent J-Code.

Effective Oct. 6, 2011, Merz reduced the price of Xeomin by nearly 20%.

Merz does not currently report ongoing development activity with Xeomin in other major markets other than Germany, e.g., U.S., European Union and Japan. Presuming Xeomin continues to show excellent safety with efficacy comparable to current products and improved stability, it may become a competitor for BOTOX.

Xeomin is generally expected to pose more of a threat to Medicis' Dysport than to Allergan's Botox. Heavy sampling has helped Merz land about 8% of the U.S. botulinium-toxin market. But, according to Xeomin's label, Xeomin can work against faical wrinkles for up to three months, while Botox's smoothing effects last up to four months.