3/16/2017
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`Restasis: the road to approval
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`Restasis: the road to approval
`The first prescription drug _for dry eye will reach the market next month,
`according to Allergan officials.
`
`Ocular Surgery News U.S. Edition, March 1, 2003
`Joan-Marie Stiglich, ELS
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`IRVINE, Calif. — When Allergan announced on Dec. 24 that Restasis had received approval from the Food
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`and Drug Administration for the treatment of dry eye disease, physicians and industry scratched their
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`collective head in bemusement. The approval seemingly came out of nowhere. How did it happen? And what
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`will the approval mean to the severe dry eye suffer?
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`It turns out that Allergan has been diligently working with federal regulators to generate the data needed for
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`approval of Restasis (cyclosporine ophthalmic emulsion, 0.05%) since it received an “approvable” letter for
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`the drug in 1999.
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`For physicians and patients there is already a confusing and crowded market of over-the-counter therapeutic
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`options. How will this new product fit in with the OTC options?
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`It has been estimated that there are 60 million dry eye sufferers worldwide, and of those 1 to 2 million are
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`subject to the most severe type of this chronic disease. So it is no surprise that clinicians and patients have
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`waited eagerly the anticipated approval of the first prescription treatment for dry eye syndrome.
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`Delay
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`“Obviously everyone has been waiting for this forever,” said David E.I. Pyott, chairman of the board,
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`president and chief executive of Allergan Inc., regarding Restasis. “We were very close to reaching the clinical
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`endpoints back in ’99.”
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`But in August 1999, Allergan received an approvable letter, which requested additional analysis of data
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`already submitted to the FDA.
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`“There was some concern about the difference between the active and the vehicle which is somewhat active
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`on its own,” said David Power, director of global eye care marketing at Allergan. “We did get an approvable
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`letter with the caveat that we needed to look further at the data regarding that.”
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`“I would say that [the approval] was thanks to the persistence of Scott Whitcup,” Mr. Pyott said. “He kept
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`going back and back and discussing the data with the agency. They managed to find a way to present a set of
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`data that met the agency’s criteria.”
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`From shortly after Allergan received the disappointing news from the FDA in August 1999 until November
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`2002, Scott Whitcup, MD, vice president, development, ophthalmology, and others were in constant contact
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`with the FDA on ways of looking at the data they already had collected. In the meantime, Allergan began a
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`second phase 3 trial of the drug, which will conclude in late April with results to be released later this year.
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`ALL 2039
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`3/16/2017
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`Restasis: the road to approval
`
`“We had already completed four large, multicenter randomized trials examining the safety and efficacy of
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`Restasis for the treatment of dry eye disease,” Dr. Whitcup said. “The clinical data demonstrated not only that
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`Restasis was safe and well tolerated, but that it led to significant improvement in tear production.
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`“The FDA has been open to considering appropriate, clinically meaningful endpoints for assessing dry eye.
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`Tear production as measured by Schinner wetting is demonstrated to be an important and clinically relevant
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`endpoint. This is the endpoint used in Restasis data,” Dr. Whitcup added.
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`“Around about Thanksgiving [2002] it began to look like we were able to present a set of data that met the
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`agency’s criteria,” Mr. Pyott said. “The fact that we are not launching until the second quarter also tells you
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`that we weren’t sure how the FDA would respond to our data.
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`“After the event you say ‘perseverance paid.”’ he said.
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`From production to market
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`Difficulty of formulation is the reason cited by Mr. Pyott for why only four pharmacies in the world formulate
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`cyclosporine. Allergan will get its cyclosporine material from a subsidiary of Novartis and will manufacture
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`Restasis in Waco, Texas.
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`Restasis, which will be available in early April, will be prepared in the same unit dose vials as Allergan’s
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`lubricating tears.
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`And at what price?
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`“We are still finalizing [pricing], but I have made it real clear that it will be a substantial premium to any
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`lubricating tear,” Mr. Pyott said, citing the company’s significant investment in time and money to bring the
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`product to launch. Allergan has also disclosed that it must pay royalties as part of their licensing agreement
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`with Novartis for cyclosporine and a separate deal with Inspire Pharmaceuticals.
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`Several investor reports have noted that Restasis could bring Allergan $100 million in annual sales. Mr. Pyott
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`speaks of a more conservative estimate — $20 to $40 million in annual sales this year — citing only 6 to 9
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`months of selling time in 2003.
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`Who will benefit?
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`Dry eye disease is incurable and often debilitating.
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`“After macular degeneration, dry eye syndrome is the biggest unmet medical need,” Mr. Pyott said. “When
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`you talk to people with severe dry eye and how many times a day they are instilling tears, these people are
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`suffering from major inconvenience, and also pain, discomfort.”
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`Approximately 60 million people worldwide use artificial tears, and 1 to 2 million suffer from moderate to
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`severe dry eye disease, estimates say.
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`Restasis: the road to approval
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`“Moderate to severe dry eye can be associated with or can lead to inflammation and may result in serious
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`damage to the ocular surface,” Dr. Whitcup said. “The incidence increases markedly with age and after
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`menopause in women and in people with systemic diseases such as Sj6gren’s syndrome, rheumatoid arthritis,
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`lupus and diabetes. In severe cases, the disease can lead to infection, corneal scarring and loss of vision.”
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`Prior to the approval of Restasis, which treats the underlying inflammation, treatment of dry eye has been
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`limited to lubricating tears, which provide palliative relief.
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`Future drug approval
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`In June 2001, Allergan and Inspire Pharmaceuticals Inc. agreed to develop and cross-license Restasis and
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`Inspire’s compound, INS365 (diquafosol tetrasodium). The terms of the agreement include the exclusive right
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`for Allergan to develop and sell INS365, with the exception of Japan, where Inspire has an agreement with
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`Santen Pharmaceuticals. Earlier this year Inspire released a statement saying that it plans to submit an NDA
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`for the compound mid-year.
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`According to information released by the company, INS3 65 stimulates natural tear and mucin production.
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`“If everything went well, we’ll be looking at somewhere around the middle of ‘04 for approval [of INS365],”
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`Mr. Pyott said. “What is exciting is that as we look at this product and Restasis it becomes clear that these two
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`products are complimentary to each other. Theoretically, the most severe patients could be using both,
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`depending on what are the underlying causes of dry eye.”
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`According to Mr. Pyott, Allergan is already the world leader in lubricating tears, not including Japan.
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`“Now we have the first real treatment for dry eye,” he said.
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`For Your Information:
`
`0 David E.|. Pyott is chairman of the board, president and chief executive of Allergan Inc. David
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`Power is director of global eye care marketing at Allergan. Scott Whitcup, MD, is vice president,
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`development, ophthalmology, at Allergan.
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`o Allergan Inc. can be reached at P.O. Box 19534, Irvine, CA 92623; (714) 246-4500; fax: (714)
`246-4971.
`
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