Saturday, December 31, 2005

Oculinum (Botox) Applications: New Products Occupy Allergan’s Plans for Future

This column was originally published in Ocular Surgery News, April 14, 1992.

Technology Update

Irving J. Arons
Ophthalmic Consulting Group
Arthur D. Little

Allergan, which was hit by a spate of negative news this past fall, also has some good news to celebrate in terms of promising products in development.

The company was beset by problems surrounding its contact lens business because of a continuing flat market. The company also met increasing competition to its PhacoFlex IOL line. Through restructuring and consolidation, and the new focus on pharmaceuticals for both ophthalmic and non-ophthalmic applications, Allergan hopes to turn itself around and look to brighter days ahead.

Announced a year ago and confirmed in recent private correspondance, Allergan has realigned itself to focus on its growing therapeutic and skin care businesses. In skin care, the company has completed Phase II studies of a patented retinoid with demonstrated efficacy for treating psoriasis as a topical formulation. The company also has secured a license from Syntex to develop and market a new topical steroid for treating inflammations of both the skin and eyes.

Product Pipeline

New ophthalmic products in the pipeline include a surgically implanted shunt to relieve intraocular pressure in treating glaucoma; new foldable silicone lens designs, including a bifocal lens; and a teledioptric system for patients with age-related macular degeneration. The latter system employs an implant that functions with specially engineered eyeglasses to provide a telescope-like effect for the visually impaired.

Several new contact lens and lens care products are in the works, including a one-bottle chemical disinfectent, an improved hydrogen peroxide solution (recently approved for marketing), and an opaque tinted contact lens.

Also for chronic treatment of glaucoma, in addition to the shunt mentioned above, Phase III results have shown promising activity for an alpha-2 agonist and preclinical development continues on prostaglandin prodrug compounds. Extended Phase III studies were recently completed on a combined Betagan (levobunolol HCL) and Propine (dipivefrin HCL) product for topically relieving intraocular pressure.

Dystonia Treatment

But perhaps the most exciting new area of development is the treatment of dystonias, or muscle disorders, with Oculinum/BOTOX (botulinum toxin Type A). Allergan acquired the rights to distribute Oculinum in December 1989 from Oculinum, Inc. (Berkeley, CA), and announced the acqusition of substantially all of the assets of the company this past July. Thus Allergan now has the rights to manufacture, market, and conduct future research into its uses.

The product was originally discovered in 1970 by ophthalmologist Alan B. Scott of Smith Kettlewell Research Institute in San Francisco, who assigned manufacturing rights to Oculinum, Inc. Allergan now assumes that responsibility.

Given orphan drug status by the FDA (providing market exclusivity for seven years following FDA marketing approval for each indication), the drug was fast tracked through clinical trials and won marketing approval in December 1989 to treat eye muscle disorders including blepharospasm and adult strabismus. The latter, although technically not a dystonia, is treated by injecting the toxin into the muscle.

The approval enabled Allergan to begin marketing the drug to treat these two disorders by injection of the purified, sterile botulinum toxin. Upon approval, the FDA has estimated that about 15,000 of the approximately 100,000 annual diagnosed cases of strabismus might be helped by the drug, and about 3000 to 5000 blepharospasm patients might be aided. However, since the drug is not yet approved for use with children, which account for the greatest number of diagnosed strabismus cases, this estimate might be high.

According to Allergan, the drug's benefits last for about three to three and a half months, and the injection can be repeated. About half of the strabismus patients treated require repeated treatments, while other muscle disorders may require chronic treatments.

Toxic Mechanism

Side effects of blepharospasm treatment include droopy eyelids and irritated eyes. The toxin is believed to work by "turning off" the muscle through paralysis. Scientists theorize that the paralysis affects muscle pairs by causing the injected muscle to lengthen, thus causing the opposing muscle to shorten. In a recent study of 677 strabismus patients, 55% showed improvements for as long as six months after treatment. In some cases, correction may become permenant provided the injected muscle is paralyzed long enough and the opposing muscle is intact.

Other dystonias for Oculinum/BOTOX under investigation by Allergan include torticollis, a debilitating condition of the neck muscles that forces the head to one side, and a non-dystonia-type problem, juvenile cerebral palsy. Additional probe studies for essential tremor and spasticity are planned.

In an excellent review article entitled, "Therapeutic Uses of Botulinum Toxin", written by Drs. Joseph Jankovic and Mitchell Brin, the doctors describe the various focal and generalized dystonias potentially treatable by Oculinum and other therapeutic agents. Dystonias are defined as involuntary sustained or spasmodic, patterned, repetitive muscle contractions, frequently causing twisting (torticollis), flexing or extending (writers cramp) and squeezing (blepharospasm) movements or abnormal postures. Several of the dystonias potentially treatable by Oculinum include blepharospasm, cervical dystonia (spasmodic torticollis), oromandibular dystonia (spasms of the jaws, mouth and tongue), spasmodic dysphonia (laryngeal dystonia), and others. In addition, high amplitude and task specific tremors that respond poorly to other pharmacological therapies, may be alleviatied by injection with Oculinum/BOTOX. In a pilot study of 51 patients with disabling tremors of the head and neck and hand, a marked to moderate reduction of the tremors was note in 67% of the patients.

Expansion Endorsement

A Consensus Development Conference Panel of NIH and the American Academy of Neurology issued a report endorsing expanded indications for Oculinum therapy. The report cites Oulinum as a promising new treatment for neck muscle spasms, mouth and jaw dystonia, facial and segmental limb dystonia, stuttering and vocal and other tremors.

It appears that Allergan has a "breakthrough therapy" on its hands, and at an annual therapy cost of better than $2000 per patient for some treatments (cervical dystonia for example), the company -- which markets the product directly to the treating physician without a detailing/selling force for the most part – stands to do quite well. Analysts estimate that total Oculinum worldwide sales could reach $175 million by 1995.


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