Status: BLA approved in April 2009; marketed internationally

Organizations involved:

Centre for Applied Microbiology Research – Manuf.; R&D; Tech.; Former

Tercica Inc. – USA mark.

Ipsen Ltd. – Manuf.; R&d; Tech..; Intl. mark.

Ipsen S.A. – Parent

Medicis Pharmaceutical Corp. – USA mark.; Canada mark.; Japan mark.

Galderma S.A. – Europe mark.; Latin Amer. mark.

Inamed Corp. – Former

Porton International plc – Former

Cross ref: See the entries above for Botulinum Toxin Products and two U.S.-marketed botulinum toxins.

Description: Dysport is a lyophilized (freeze-dried) formulation of botulinum toxin type A complex (abobotulinumtoxinA ). The botulinum toxin A in Dysport is produced by fermentation of the bacterium Clostridium

botulinum type A, Hall Strain. It is purified from the culture supernatant by a series of precipitation, dialysis, and chromatography steps. The neurotoxin complex is composed of the neurotoxin, hemagglutinin proteins and non-toxin non-hemagglutinin protein. AbobotulinumtoxinA has a molecule weight ranging from 500-900 kDa, unlike the toxin in BOTOX, which has a consistent molecular weight of 900 kDa, and the toxin in Xeomin, which is uncomplexed with a molecular weight of 250 kDa.

The potency of this product is different than that of BOTOX, e.g., about four times the dosage (in Units) of Dys-port is injected for many of the same uses as BOTOX and MyoBloc. Each product has its own potency assay, and Units are not comparable. One BOTOX unit (U) is approximately equal in activity to that of 3-5 U of Dys-port. Differences in potency may be due to the vehicle and dilution schemes used prior to potency testing, packaging, and other factors. Dys-port is reconstituted in saline, like BOTOX, but its potency is determined using a gelatin phosphate buffer, which increases potency relative to saline.

In the U.S., one unit of Dysport corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice. The method for performing the assay is specific to Dysport. Due to differences in specific details such as vehicle, dilution scheme and laboratory protocols for various mouse LD50 assays, Units of biological activity of Dysport are not interchangeable with Units of any other botulinum toxin or any toxin assessed with any other specific assay method.

In the U.S., Dysport is available in cartons containing either a single or two 500 Unit vials or a single 300 Unit vial of Dysport as a a sterile, single-use, 3 mL glass vial. The Medication Guide is inserted inside the carton with the vial(s), with a Medication Guide provided for each vial. Dysport contains a unique hologram on the vial label and carton to protect against counterfeiting.

In the U.S., Dysport for glabellar lines is packaged in 300 Unit vials.

Dysport vials (both 500 and 300 Units) also contain 125 µg human serum albumin and 2.5 mg lactose. may contain trace amounts of cow’s milk proteins.

The U.S. dating period for Dysport is 12 months from the date of manufacture when stored at 2-8 °C (refrigerated).

Nomenclature: Botulinum Toxin A/Ipsen [BIO]; Reloxin [TR formerly used by Medicis in the U.S. for aesthetic uses]; Dysport [TR used by Ipsen outside U.S.; trade name in U.S. for all indications:]; Azzalure [TR in Europe used by Galerma for aesthetic indications:]; Clostridium botulinum type A neurotoxin complex [INN]; Neurotoxin (Clostridium botulinum A strain Hall heavy chain), complex with hemagglutinin (Clostridium botulinum A strain Hall) and neurotoxin (Clostridium botulinum A strain Hall light chain) and protein NTNH (non-toxin non-hemagglutinin) (Clostridium botulinum A strain Hall) [CAS]; mixture of botulinum neurotoxin type A (BoNT/A, EC 3.4.24.69, Bontoxilysin-A), hemagglutinin component HA33 and botulinum neurotoxin type A1, nontoxic-nonhemagglutinin component, NTNH (EC 3.4.24.69, type A progenitor toxin nontoxic-nonHa), components of the neurotoxin complex (Clostridium botulinum A strain Hall) [CAS]; botulinum toxin type A complex [SY]; 953397-35-8 [CAS RN]; CNT52120 [SY]; NDC 15054-0500-1; NDC 15054-0500-2; NDC 99207-500-30 [NDC]

Companies.: This product is marketed in the U.S. for therapeutic indications: as Dysport by Tercica Inc. a subsidiary of Ipsen, and licensees. It is marketed internationally, particularly for therapeutic (vs. aesthetic) uses by Ipsen. Galderma markets Dysport (as Azzalure) for aestheic indications: in Europe, Brazil, Argentina and Paraguay.

Medicis markets Dysport (using the trade name Reloxin prior to approval) in the U.S. for aesthetic/cosmetic indications: (initially glabellar lines). Physicians in the U.S. may place orders for Dysport for aesthetic indications: through McKesson, a major pharmaceutical distributor, while Medicis concentrates on marketing.

Dysport was developed and the bulk toxin was originally manufactured by the Center for Applied Microbiology and Research (CAMR; Porton Down, U.K.), Microbiological Research Authority, formerly the Public Health Laboratory Service (PHLS). Ipsen financed refurbishment of CAMR facilities for manufacture of Dysport. Finishing of the product was performed by Ipsen Biopharma Ltd. at its facilities in Wrexham, Wales, U.K., CBER/FDA est. no. 1787.

With its U.S. approval, Ipsen reports that it now fully Mmanufactures Dysport at its facilities in Wrexham, Wales - "The Wrexham site gathers the manufacturing, product formulation, packaging and testing activities for the entire production of botulinum toxin type A."

Dysport is marketed in Europe and many other countries by Ipsen Ltd., a subsidiary of Ipsen S.A. It was formerly marketed by the Speywood Pharmaceutical subsidiary of Porton International plc. Beaufour Ipsen, now Ipsen, acquired Speywood in 1994.

In Dec. 2001, Ipsen S.A. granted Inamed Corp. exclusive rights to market botulinum toxin A for cosmetic uses in U.S., Canada and Japan.

In Jan. 2005, Ipsen S.A. granted Inamed Corp. exclusive rights to market Dysport for treatment for wrinkles outside of North America and Japan. Inamed already had exclusive license for dermo-cosmetic applications outside of North America and Japan.

In early 2006, Inamed was acquired by Allergan, the manufacturer and marketer of Botox and Botox Cosmetic (see entry above), and Inamed returned Reloxin/Dysport marketing rights to Ipsen in early 2006 to allow the merger to proceed (alleviate monopoly/antitrust concerns; with Allergan being the manufacturer and marketer of BOTOX and BOTOX Cosmetic). The termination of the licensing deal between Ipsen and Inamed triggered a $10 million payment to Ipsen.

In March 2006, Ipsen exclusively licensed U.S., Canadian and Japanese marketing rights for aesthetic uses to Medicis Pharmaceutical Corp. Ipsen retained marketing rights for therapeutic uses in these territories. The agreement extends until Dec. 2036. Upon FDA approval, Medicis paid Ipsen a $75 million milestone fee.

In Feb. 2007, Ipsen entered into a partnership with Galderma S.A. for development and marketing of Dysport (marketed in Europe by Galderma as Azzalure) for aesthetic indications: in Europe and certain other territories. Ipsen granted Galderma exclusive rights to develop, promote and distribute a specific formulation (Azzalure) for the aesthetic medicine indications: product in the European Union, Russia and certain territories of the Middle East and Eastern Europe. Ipsen also granted Galderma first rights of negotiation for aesthetic medicine indications: in the rest of the world, excluding the U.S., Canada and Japan, as well as rights for future formulations. Galderma paid Ipsen an upfront payment of Euros 10 million and will pay up to Euros 20 million, in additional to milestone payments, including market approvals and product launches in certain territories and an additional payment, to be negotiated, with respect to Russia. In addition, Galderma will pay royalties to Ipsen, which will manufacture and supply Galderma’s finished product at a fixed supply price. The total of transfer price and royalties received by Ipsen will be ~40% of Galderma’s net sales. The agreement is for an initial term expiring in Sept. 2019 and will be extended for a total of 30 years upon the achievement of a major milestone. Galderma will carry out and fund any future development activity for new aesthetic indications:. Ipsen will own all regulatory approvals and all data arising from development activities, while Galderma will own the trademark and/or trademark rights in aesthetic medicine indications:.

Manufacture: With its manufacture in Europe, where animal testing is more of a public concern and issue than in the U.S., Ipsen has committed to “Refinement, Reduction and ultimately Replacement of laboratory animals, in assaying botulinum toxin.” The company has been working for some time to develop alternative testing methods, which were reviewed in the June 2006 issue of Alternatives To Laboratory Animals [34(3):305-313]. Ipsen’s research is currently focussed on three alternative testing methods: an endopeptidase activity assay; an ex vivo neuromuscular junction assay; and an enzyme-linked immunosorbent assay (ELISA). Ipsen is currently evaluating each of these alongside the standard tests. The company anticipates that the outcome of this work could mark the end of animal testing in the manufacturing of this product.

FDA class: Biologic BLA

Approvals: Date = 20090429, BLA BL 125274/0; Indications: = treatment of cervical dystonia; and Reloxin received a supplemental BLA for gabellar lines (and with this, abandonment of use of Reloxin as a trademark)

Indications: [Full text of the "Indications: and Usage" section of Dysport product insert/labeling, 10/1/2009]:

DYSPORT is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for:

• the treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain in both toxin-naïve and previously treated patients

• the temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adult patients < 65 years of age

Status: Dysport received its first approval in the U.K. in 1991 (granted to Porton Intl.).

Upon its U.S. approval, Dysport was approved in 76 countries for therapeutic use and in 27 countries for aesthetic use. Dysport has been approved and used for therapeutic indications: in the U.K. since 1991.

On Dec. 5, 2007, Ipsen filed a BLA (STN 125274/0) for Reloxin for aesthetic indications:, and a BLA for Dysport for cervical dystonia.

On Jan. 31, 2008, FDA refused to file Ipsen's BLA for Reloxin for aesthetic indications:, citing it as incomplete. FDA's concerns reportedly related primarily to sponsorship and ownership of the filing (administrative issues), "and did not reference any substantive deficiencies." Also on Jan. 31, 2008, FDA accepted a BLA filed by Ipsen for Dysport for treatment of cervical dystonia.

On March 17, 2008, Ipsen and Medicis refiled their BLA (as BLA STN 125286/0) for Reloxin for aesthetic indications: (glabellar lines), addressing FDA concerns. This BLA was later converted to efficacy supplement STN 125274/1.

On Sept. 30, 2008, Ipsen reported that FDA would not complete its first-cycle review of the Dysport BLA until the end of the year. The PDUFA date had been Oct. 7, 2008. FDA did not request any additional safety or clinical studies and the regulatory delay was not expected impact the anticipated U.S. launch in 2009.

On Dec. 29, 2008, FDA issued Ipsen a Complete Response Letter for its BLA for Dysport for cervical dystonia. FDA did not request any new clinical studies prior to approval. The Letter requested additional information, including the finalization of the Risk Evaluation and Mitigation Strategy (REMS) and of the draft labelling, as well as a Safety Update Report. FDA also confirmed in its Establishment Inspection Report that the manufacturing process for Dysport in its Wrexham (Wales) facility is in compliance with cGMPs.

In Jan. 2009, FDA further extended the PDUFA date to April 13, 2009. Ipsen reported that FDA had confirmed in an inspection report that the manufacturing process for Reloxin in its Wrexham, Wales facility was in compliance with current Good Manufacturing Practices.

On March 13, 2009, the U.K. approved Azzalure from Galderma "for the temporary improvement in the appearance of moderate to severe glabellar lines seen at the frown (vertical lines between the eyebrows), in adult men and women aged 65 years and under, when the severity of these lines has an important psychological impact on the patient." The approval was based on several clinical trials involving more than 2,600 patients, which confirmed the safety and efficacy of Azzalure. At the time, 15 other European countries had approved aesthetic use (glabellar lines) of Azzalure.

FDA did not refer the BLA to an advisory committee because Dysport was not the first product in its class, the clinical study designs were acceptable, no significant safety or efficacy issues were raised, no significant public health questions were raised regarding the role of the product in the diagnosis, cure, mitigation, treatment or prevention of a disease, and outside expertise was not considered necessary.

On April 29, 2009, FDA approved Ipsen's BLA for Dysport for cervical dystonia (with orphan status) and a sBLA for Reloxin for glabellar lines. Ipsen launched Dysport for the treatment of cervical dystonia in the U.S. in the second half of 2009; and Medicis anticipated U.S. launch 30-60 days from approval.

FDA approval included a Risk Evaluation and Mitigation Strategy (REMS) for Dysport designed to help prevent medication errors related to the lack of interchangeability of Dysport with other marketed botulinum toxin products, and ensure that the potential benefits of treatment with Dysport outweigh any potential risk of the spread of toxin effect beyond the injection site. The labeling contains a boxed warning about the potential distant spread of all botulinum toxin products, including Dysport. The REMS included: 1. A survey of patients’ understanding of the serious risks of Dysport; 2. A survey of prescribers’ understanding of the serious risks of Dysport and the lack of interchangeability of Dysport units with those of other licensed botulinum toxin productsl 3. A report on periodic assessments of the distribution and dispensing of the Medication Guide in accordance with 21 CFR 208.24; 4. A report on failures to adhere to distribution and dispensing requirements, and corrective actions to address non-compliance; 5. An assessment of use data including:a. extent of use (denominator estimates, and b. number of patients by agel 6. A summary of reports of all potential or diagnosed cases of distant spread of botulinum toxin effects after local injection with Dysport. 7. A summary of reports of all medication errors involving interchangeability of Dysport units with those of other licensed botulinum toxin products.

Also as part of its FDA approval, Ipsen committed to perform a safety study assessing distant spread of toxin effects after multiple administrations of Dysport during a minimum period of 12 months in at least 100 pediatric patients (ages 2-17 years) and 100 adult patients (approximately half upper, and half lower extremity spasticity), along with data assessing the effects of Dysport on blood glucose and alkaline phosphatase as a marker of bone metabolisn; a juvenile rat toxicology study is required to identify the unexpected serious risk of adverse effects on postnatal growth and development; an embryo-fetal development study is required in rabbits to identify the risk of adverse effects on embryo-fetal development; a study to establish tighter potency acceptance criteria for the qualification of new reference standards so that the product is dosed properly. Ipsen also will perform multiple randomized, double-blind, controlled, multiple fixed doses, parallel group clinical studies of Dysport in botulinum toxin-naïve children age 2-17 years with lower and upper extremity spasticity. Ipsen will also develop a 125U single use dosage form appropriate for dermatologic indications.

No centralized EU approval granted - country-by-country.

Trials: In July 2006, a pilot study was reported comparing the migration characteristics of BOTOX and Dysport. Dysport had a significantly larger area of migration beyond the targeted area of injection (not a desirable characteristic) compared to BOTOX. Different migration characteristics among botulinum toxin type A formulations may result in different tolerability profiles of botulinum toxin A products. Preclinical studies suggest that migration within muscle is inversely related to molecular size, and that smaller toxin proteins diffuse more. Thus, the larger BOTOX molecule may minimize migration outside of targeted tissue. Each patient received one injection of BOTOX (4 U) on one side of their forehead, one injection of Dysport (12 U) on the other side of their forehead (reflecting the currently recommended dose ratio of 1:3 Botox to Dysport), and one injection of preservative-free saline (placebo) in the center of their forehead. All injections were of identical volume (0.1 mL). Overall, in 11 of 12 study participants, the area of anhydrosis (no sweating) was significantly larger (an average of 77% larger) with Dysport than with BOTOX (p=.005)

The BLA glabellar lines indication was supported by clinical studies in ~2,900 patients at more than 80 clinical study sites.      

The BLA for cervical dystonia was primarily supported by two well-controlled, randomized, doubleblind, placebo controlled, single dose, parallel group studies in treatment-naïve cervical dystonia patients. The principal analyses from these trials provided the primary demonstration of efficacy involving 252 patients (121 on Dysport, 131 on placebo) with 36% male and 64% female.

Medical: For cervical dystonia, the initial dose of DYSPORT is 500 Units given intramuscularly as a divided dose among the affected muscles with re-treatment every 12 to 16 weeks or longer, as necessary, based on return of clinical symptoms with doses administered between 250 and 1000 Units to optimize clinical benefit. Re-treatment should not occur in intervals of less than 12 weeks. Titration should occur in 250 Unit steps according to the patient’s

response

For glabellar lines, a total dose of 50 Units of DYSPORT™, divided in five equal aliquots of 10 Units each, should be administered to affected muscles to achieve clinical effect. Re-treatment should be administered no more

frequently than every 3 months.

In the U.S. practice, the approved Dysport starting dose for the treatment of cervical dystonia in botulinum toxin-naïve and previously treated patients is 500 Units. Further doses to treat cervical dystonia should be given no less than 12 weeks apart. Depending on patient response, doses may be increased or decreased in 250 Unit increments. The maximum recommended dose for cervical dystonia is 1 000 Units every 12 weeks.

U.S. physician injectors who have worked with both Botox and Dysport have reported that, while the two are relatively comparable, they sometimes prefer one over the other in certain facial areas, due to differences in the onset of results, and spread of effect. Dysport is faster-acting and has a greater 'spread' (giving a more 'natural' look); while Botox(R) tends to remain more localized, allowing for greater precision and predictability in the treatment area, but possibly requiring more injections in the course of a treatment.. The major benefits of Dysport to the cosmetic patient include fewer injections, and treatments will likely last a little longer. Dysportresults might last up to a month or even two beyond that of Botox -- which could be a bonus as long as the outcome is what the patient wanted; if not, he/she has that much longer to live with the results.

Market: Total Dysport sales were 82.5 million euros (~$107.9 million) in 2005, and about $90 million in 2003. Sales have generally been growing at an average annual growth rate of 34.7% since 1991. Ipsen apparently has not reported Dysport sales in recent years.

In 2009, upon FDA approval, it was reported that "Patient exposure is estimated to be above two million single treatment cycles, representing more than 600,000 patients year of treatment."

Dysport was launched in the U.S. at prices somewhat lower than those for Botox. [Prices not yet reported in the 2009 Red Book].

As discussed in the Botulinum Toxins Products and BOTOX entries above, BOTOX from Allergan dominates the world market for botulinum toxins, currently with ≥85% market share. Even when Dysport enters the U.S. market, projected in about two years, BOTOX/BOTOX Cosmetic will be sufficiently established and approved for more indictions, such that Dysport will likely have a difficult time gaining significant market share (unless sold at a significantly discounted price)

Ipsen stated, "The US aesthetic sector alone is thought to be worth $300-$400 million," and with approval of Reloxin [now Dysport from Medicis] in the U.S., hopes to capture a portion of this market from BOTOX.

In the U.S., Medicis also markets other aesthetic products, including hyaluronic acid products (Restylane and Perlane; see related entries).

In March 2010, Medicis introduced a U.S. marketing campaign that offers Dysport users discounts and a patient satisfaction rebate guarantee. The campaign, which ran through April 30, was intentionally designed to elevate Dysport’s image and cannibalize market share of Botox, the market leader. The Dysport promotion, running on the product’s Web site and in a few glossy magazines like US Weekly, offered a $75 rebate check on an initial Dysport treatment for wrinkles between the eyebrows, a procedure that can cost consumers $300 to $500. Satisfied customers can receive a $75 rebate on a follow-up Dysport treatment, while dissatisfied customers who want to switch can receive a $75 rebate on a Botox treatment. This unprecedented and novel campaign showed the lengths that Medicis has been willing to go through to garner market share from Botox. The use of product rebates and drug discounts is mostly used to market so-called vanity drugs (like Latisse, Botox and Dysport) which have been approved by FDA for clinical use but are not covered by medical insurance.