Trend

Changing faces

Wiping away wrinkles and putting smiles on the faces of patients, Botox seems to be effectively entering various therapeutic areas, which could change its functional range forever. Manjusha Morgaonkar explores

Botox has come a long way from smoothening frown lines to discovering new remedies to treat a variety of indications. Slipping every now and then between controversies regarding its safety and side-effects, Allergan, the company that developed Botox, hopes that its applicability to a range of therapeutic indications will change consumer perception of it being only for cosmetic indications. Rajkumar Narayanan, Vice President and Managing Director--Emerging Markets (Asia), Allergan, says, "As Botox becomes more popular in India, we anticipate that more and more patients will approach their physician to find out if Botox is suitable for their medical conditions." Narayanan says that the history of Botox is a remarkable story of how one of the most potent substances found in nature has come to be understood and ultimately harnessed for the benefit of patients with serious neuromuscular and other disabling conditions. New uses for Botox will continue to evolve as Allergan works in partnership to explore novel applications in areas that hold enormous promise for addressing medical needs and enabling patients to live life to their fullest potential.

Indications

Around the world, Botox has been approved in more than 75 countries for 20 different indications. The approved 17 therapeutic indications (other than the three cosmetic indications) for Botox vary from country to country--achalasia (failure of the lower oesophageal sphincter to relax), adult spasticity, anal fissure, back pain, blepharospasm (involuntary blinking), bruxism (grinding of the teeth, typically accompanied by clenching of the jaw), cervical dystonia (a neuromuscular disorder involving the head and neck), essential tremor (neurological disorder evoked by intentional movements), headache (migrane), hemifacial spasm (involuntary contraction of the muscles), juvenile cerebral palsy (foot deformity), multiple sclerosis (a chronic, inflammatory, demyelinating disease that affects the central nervous system), myoclonic disorders, overactive bladder (a sudden involuntary contraction of the muscle wall of the urinary bladder), spasmodic dysphonia (voice disorder), strabismus (crossed eyes), and VII nerve disorder. Botox is a purified protein that works by blocking overactive nerve impulses that trigger excessive muscle contractions or glandular activity. In India, Botox was first approved in 1994 for the treatment of strabismus and blepharospasm. The other US FDA approved indications in India for Botox include cervical dystonia and juvenile cerebral palsy, approved in July 2002; adult spasticity in July 2004 and primary axillary hyperhidrosis (excessive underarm sweating) in March 2006. The effect is temporary and lasts from approximately one to six months, depending on the individual patient and indication.

Growth rate

Sales of Botox have maintained a double-digit growth rate in the therapeutic use segment, it is only its cosmetic avatar that has been publicised. "Over the last five years it is driven primarily by new and approved indications, a focused sales and marketing organisation, and physician education. Prior to 2007, Botox sales for therapeutic use accounted for a bigger portion of the total Botox business than sales of Botox cosmetic", Narayanan says. Based on internal information and assumptions, therapeutic sales in the year 2007 accounted for around 50 percent of the total Botox sales and grew at the rate of about 19 percent compared to 2006. Over the course of nearly 20 years, millions of patients worldwide have been treated therapeutically with Botox. "Botox has led us into new medical areas and has permitted us to go from an R&D expenditure of $100 million to an estimated $760 million," Narayanan says. "Allergan is now pursuing an advanced research to develop 'next generation' neuromodulator therapies and other treatments for neurological conditions including chronic migraine, post-stroke spasticity, overactive bladder and pain management," he added.

Plans to overcome competition

In an increasingly competitive market, Botox commands an estimated 85 percent of the global market share and has increased its share in the top ten global markets to 91 percent. Furthermore, in the fourth quarter of 2007, Allergan enjoyed even stronger sales growth for Botox outside US, precisely in those markets where they already had competitions. Narayanan says that Allergan has competition overseas and will face one in the United States by Dysport/Reloxin, which they anticipate in early 2008. "Brand loyalty and trust cannot be overstated in this growing market because people want to trust a company that has demonstrated its commitment to safety, quality assurance and patient care. We are confident that Botox has a longer safety history than Dysport, and we are well prepared to compete with Dysport/Reloxin in the United States. We look forward to the competition. Frankly, the more we are compared to other products, the better we look," he adds.

Out of harm's way?

With more than 3,000 publications on botulinum toxin type A in scientific and medical journals, results of dozens of clinical trials involving more than 10,000 patients, and having been used in clinical practice to treat more than a million patients worldwide, Botox is a widely researched medicine, says Narayanan.

FDA inquiries mostly relate primarily to high dose medical uses of Botox, particularly for the management of juvenile cerebral palsy. He says, "Our own analysis indicates that when a problem arises in the use of the product for juvenile cerebral palsy, it tends to either be because the patient was already very high risk and sick and/or because a significant amount of Botox was administered."

As per Narayanan, the most commonly reported use of botulinum toxin among the cases currently under review by the FDA are treatment of limb muscle spasticity associated with cerebral palsy, where Botox doses ranged from 6.25 to 32 units/kilogram. Among the adult cases that were serious, including hospitalisation, none required intubation or ventilatory support, and no deaths were reported.

In addition to the product's heritage and its proven long-standing safety and efficacy record, Allergan is in frequent dialog with the FDA to ensure proper labelling for Botox and also submits information on all adverse events that are received, whether or not they are considered related to the product. "In collaboration with the FDA and other regulatory agencies around the world, Allergan regularly reviews safety information and updates the label for Botox as appropriate," says Narayanan.

Furthermore, the product labelling for Botox already notes rare select cases of fatal outcomes in which some patients had significant debilitating conditions or may have had a history of cardiovascular disease or other co-morbid conditions. And the Botox labels specifically warn that patients with pre-existing neuromuscular disorders may be at increased risk of clinically significant systemic effects from typical doses of Botox. "Allergan will discuss with the US FDA whether further clarification about the definition of juvenile cerebral palsy as a 'neuromuscular' disorder is needed in the US Botox label, and make any appropriate changes, as needed, following the agency's conclusion," states Narayanan.

R&D plans

The development of new applications for Botox is continuing in new areas where unmet medical needs are the greatest. "Allergan is moving forward with phase III studies for chronic migraine in US. It has also initiated a clinical program for Botox in the treatment of benign prostatic hypertrophy and has begun working on a next-generation neuromodulator with more selective action targeted to specific cell receptors for pain management and spasticity treatment," Narayanan reveals.

For almost 20 years, Botox has been the foundation for Allergan's global leadership position in neuromodulator therapy and neurosciences. Speaking on company's investment plans, Narayanan says that Allergan has committed approximately $800 million in Botox research and clinical development. In 2007, Allergan invested $646 million into R&D programs which marked an increase of 36 percent over 2006 and the largest increase in Allergan's history. Whereas in 2008, Allergan plans to invest $760 million into R&D ($120 million more than 2007 and around 17 percent of estimated net product sales).

The research on Botox for potential treatments is driven not only by Allergan, but by other companies and physicians as well. Keeping this in mind, it will be a great challenge for the company as it will have to decide on the various therapeutic focuses that it wishes to pursue as per its resources, and the effort that it is willing to put into discovering novel therapies that will answer the prayers of the suffering.

manjusha.morgaonkar@expressindia.com