Specialty Pharmaceuticals: Therapy Class Review: Macular Degeneration

With the novel agents in the age-related macular degeneration pipeline, drug makers are taking advantage of an opportunity for innovation.

Disease Overview ^1-3

Age-related macular degeneration (AMD) is an eye condition where there is a deterioration or breakdown of the macula, a small area in the retina that allows a person to see fine details clearly. When the macula does not function correctly, a person’s central vision can be affected by blurriness, dark areas, or distortion. Macular degeneration affects the ability to see near and far, and can make some activities—like threading a needle or reading—difficult or impossible.

There are 2 main types of AMD. Dry AMD is characterized by the presence of yellow deposits, called drusen, in the macula. Drusen is mostly found in individuals older than 60 years and may be detected during a dilated eye exam. In general, drusen do not cause changes in vision; however, as they grow in size and number, they may lead to a dimming or distortion of vision that individuals find most noticeable when they read.

There are 3 stages of dry AMD: early, intermediate, and advanced dry AMD. In more advanced stages of dry AMD, there is also a thinning of the light-sensitive layer of cells in the macula, leading to atrophy or tissue death. As the dry form worsens, abnormal blood vessels may begin to grow behind the macula, usually near drusen deposits. This abnormal growth of vessels leads to the “wet” form of the disease.

Wet AMD occurs when abnormal blood vessels behind the retina start to grow under the macula. These new blood vessels tend to be very fragile and often leak blood and fluid. The blood and fluid raise the macula from its normal place at the back of the eye. Damage to the macula occurs rapidly, resulting in loss of central vision. Wet AMD is considered to be advanced AMD and is more severe than the dry form. An early symptom of wet MD is that straight lines appear wavy.Wet AMD is always preceded by the dry form of the disease.

Common risk factors for AMD include smoking, obesity, race (whites are more likely to lose vision than African Americans), family history, age, high blood cholesterol levels/high intake of saturated fat and cholesterol, and high blood pressure.

Economic Impact ^4-8

• In a prospective cohort study evaluating the direct costs of blindness for patients enrolled in managed care, the total mean health care charges related to blindness per person in the first year were $20,677, whereas the mean charges for nonblind patients were $13,321.

• In 2004, the estimated total financial cost of major visual disorders among US residents 40 years or older was $35.4 billion. The direct medical costs for AMD were roughly $575 million. This is expected to increase to an estimated $845 million during the next 15 years.

• Excess medical expenses that are tied mainly to home health care/nursing expenditures for people who are visually impaired or blind are estimated to be $1000 to $2000 per year.

Demographic/Prevalence Data^9-13

• 1.6 million Americans 50 years and older have AMD; 1.8 million Americans 40 years and older have advanced AMD.

• 7.3 million people with intermediate AMD are at substantial risk for vision loss.

• More women are affected than men.

• The government estimates that by 2020 there will be 2.95 million individuals with advanced AMD.

• 3.8% of Americans aged 50 to 59 years have either intermediate or advanced AMD. By age 70 to 79 years, this increases to 14.4%.

• Dry AMD is the more common form. More than 85% of all AMD is the dry form.

• Wet AMD leads to more vision loss than dry AMD. It is the leading cause of blindness in people older than 65 years. Two-thirds of advanced AMD patients have the wet form.

• By 2020, AMD will affect almost 3 million Americans.

Current Market Observations¹⁴

AMD is an undertreated disease that predominately affects the elderly. Treatment of AMD represents considerable commercial potential for developers of innovative drug therapies. During the next few years, novel antiangiogenic drugs, which stop the growth of new blood vessels, are expected to outgrow the success of the photodynamic therapy (PDT) verteporfin (QLT/ Novartis’s Visudyne). Agents with better efficacy against vision loss are the greatest unmet need in AMD.

The wet AMD therapeutic sector by itself is expected to be worth $1.84 billion in 2010. With many innovative angiogenesis inhibitors in late-stage clinical development with new drug applications soon to be filed, this segment is on the brink of a revolution, whereby patients can gain access to vision-saving therapies. Improving on the conventional therapies currently in use, the new treatments are likely to not only prevent the progression of disease, but also cause the swollen blood vessels to regress, thereby hopefully restoring some lost visual capabilities.

Dry AMD currently has no effective treatment, so market opportunities are available for a first-to-enter product in this market. Blockbuster status would be guaranteed for a drug tackling the more prevalent dry AMD.

Many thought-leading ophthalmologists anticipate that an expanding drug-treated patient pool, together with the increasing use of combination therapy consisting of PDT and 1 or more emerging therapies, will fuel dramatic growth of the AMD pharmaceutical market. With the move to combination therapy, current products and new pharmacologic therapies for AMD are expected to enjoy consistent and considerable sales growth.

The global macular degeneration market was valued at $1.054 billion in 2009. It is expected to grow to $2.090 billion with a compound annual growth rate of 10.3% by 2016. This growth is primarily attributed to the increase in the aged population worldwide. The current competition in the macular degeneration market is strong and is dominated by vascular endothelial growth factor (VEGF) targetor products. Products in the market have different efficacy and safety profiles. The presence of many promising drugs, such as Retaane, Zinthionein, and Photrex, and other first-in-class drugs in the advanced stages of clinical development, suggest increased competition in the future once these products are successfully launched to the market.

Visudyne (Novartis) was the first FDAapproved drug for wet AMD in 2000. Macugen (Enzon/Gilead), a VEGF antagonist, was approved in December 2004 for patients with wet AMD. In the second half of 2006, the FDA approved Lucentis (Genentech), a VEGF-A inhibitor for wet AMD patients. The current competition in the macular degeneration market has proved to be efficacious and fairly successful in meeting the market demand. These products have disease-modifying properties and show relief from diseaseassociated symptoms. Symptomatic relief for the patient varies according to the dosage and drug type.

Based on an analysis reported in a new report called “Macular Degeneration— Drug Pipeline Analysis and Market Forecasts to 2016,” the macular degeneration therapeutics pipeline is strong and contains 114 molecules. A majority of entities in the pipeline—more than 68%—are first-in-class and are in various phases of clinical development. The rest are me-toos and combination therapies.

These first-in-class molecules have distinct advantages over the currently marketed products in terms of overall survival rates and efficacy and safety profiles, and have the potential to satisfy the market’s unmet needs. If approved, these products will stimulate intense competition in the market, and the existing market leaders will need to respond quickly in the race to develop a new blockbuster drug.

Some products currently under clinical investigation are expected to receive approval from regulatory agencies in the next few years. Essentially, the global macular degeneration market is heading towards an increasingly competitive landscape with more dynamism expected. Strong pipeline candidates are expected to intensify future competition.

Photrex (Miravant Medical Tech) and Retaane (Alcon) have completed Phase III clinical studies and are waiting for FDA approval. There are many other products in Phase III, such as AL-8309B, alprostadil, zinthionein, VEGF Trap-Eye, microplasmin, and combination therapies such as ranibizumab plus verteporfin and BA-LVR plus ST-LVR. The pipeline products are being developed to have improved features such as reduced risks associated with intake, better efficacy regardless of the degree and length of illness, the ability to slow down the progression of the disease, and reduced side effects.

Pipeline Leverage Points

As new products with different mechanisms of action are marketed, more physicians are going to start using combination therapy to obtain better and longer lasting results. Currently, the standard for wet AMD is using a single agent. Managed care plans can expect to see the costs related to treating AMD rise not only with the advent of newer, better products, but also because of the increase in use of multiple products. Physicians are also expected to start switching between products if less than favorable results are obtained after using an initial product.

In addition, off-label use of Avastin has quickly gained popularity among ophthalmologists because it costs considerably less than Lucentis. Avastin is closely related molecularly to Lucentis. Eye doctors have argued that Avastin has been shown to be highly effective, and possibly longer lasting than and comparable in results to Lucentis. Due to the increase in offlabel use, and probably the bottom line effect on sales of Lucentis, Genentech— the maker of both products—launched a strategy to limit the availability of Avastin for ocular uses as of January 1, 2008, citing safety issues.

After much protest from physicians and organizations, Genentech will make Avastin available directly to physicians, hoping to circumvent compounding pharmacies from making patient-specific prescriptions. In response to all the speculation, the National Eye Institute has a head-to-head study of both products currently under way. The study is expected to be competed in late 2011. PT

Table 1. Current AMD Therapies

Brand (Manufacturer)

Generic

Class of Drugs

Current Indication(s)

Dosing Frequency *

Route of Administration

Approval Date

Patent Expiration

Limited Distribution

Lucentis

(Genentech)

Ranibizumab

Monoclonal antibody

ophthalmological agent

· Wet AMD

·

· Macular retinal edema-retinal vein thrombosis

· 0.5 mg/0.05 mL every 28 days. After 4 injections, can change to every 3 months.

· 0.5 mg/0.05 mL every 28 days

Intravitreal (in the eye) injection

06/30/06

06/30/2020

Y

Macugen (Enzon/Gilead)

Pegaptanib sodium B

Ophthalmologic agent (Anti-VEGF inhibitor)

· Wet AMD

0.3 mg every 6 weeks

Intravitreal injection

12/17/04

2017

Y

Visudyne (Novartis)

Verteporfin

Photosensitizing agent

· Wet AMD

·

· Histoplasmosis

·

· Myopia

6 mg/m² every 3 months

Intravenous Injection

04/12/00

2016

Y

*Dosing frequency reflects the standard adult dose only. Pediatric and dose reduction/adjustment frequencies have been omitted.

AMD = age-related macular degeneration; VEGF = vascular endothelial growth factor. Adapted from references 14, 15.

Table 2. AMD Pipeline

Brand (Manufacturer)

Generic

Drug Class

Phase (Fast-track, III, NDA/BLA)

Current Indication(s)

Pending Indication(s)

Dosing

Route of Administration

Estimated Approval

Comments

Avastin (Genentech)

*being studied by National Eye Institute

bevacizumab

monoclonal antibody

Phase III

Metastatic breast cancer

Metastatic colorectal cancer

Nonsmall cell lung cancer

Metastatic renal cell cancer

Glioblastoma

Wet AMD

1.25 mg every 4 weeks

Intravitreal (in the eye) injection

Trial looking at clinical evidence to treat. Not being done by manuf., therefore no labeling change anticipated. Study is expected to be completed late 2011 and published early 2012

Avastin and Lucentis are derived from the same monoclonal antibody and are molecularly similar. Given this, and its low cost, Avastin has sparked much interest from investigators for the treatment of AMD. Most of the US studies are small and investigator driven. The larger trials are mostly overseas and have limited sponsorship from the manufacturer.

AVE005

(Bayer/

Regeneron)

Aflibercept/ VEGF-Trap-eye

Angiogenesis inhibitor

Phase III (Phase III for lung cancer & prostate cancer)

None

Wet AMD

(CNV)

0.5 or 2.0mg every 4 or 8 weeks

Intravitreal injection

Mid 2010

Blockade of VEGF, which can prevent abnormal blood vessel formation and vascular leak, has proven beneficial in the treatment of wet AMD. Two phase III trials met non-inferiority end points in comparison to ranibizumab in December 2010 (COPERNICUS trial). The MYRROR trial starting enrollment in January 2011 is hoping to expand the indication to CNV

Bevasiranib Sodium

(Opko Corp)

Bevasiranib sodium (Cand5)

Not yet determined.

Bevasiranib is a small interfering RNA (siRNA) drug designed to silence the genes that produce vascular endothelial growth factor (VEGF)

Phase III

None

Wet AMD

1.0, 2.0 or 2.5 mg every 8-12 weeks

Injection

Discontinued

In clinical trials, Bevasiranib is started after pre-treatment with 3 injections of Lucentis.

Trials discontinued due to an analysis of the preliminary data conducted by an independent data monitoring committee which demonstrated that the trial was unlikely to meet its primary end point

PHOTREX /SnET2 (Miravant Medical Tech)

Rostaporfin

Phototherapy

NDA submitted 2005

None

Wet AMD

0.5-0.7 mg/kg

Intravenous infusion followed by phototherapy (light therapy)

Unknown

FDA issued an approvable letter for Photrex in 2005. In the letter they requested a confirmatory phase 3 trial before final approval can be granted. Phase 3 trials are currently underway.

Retaane

(Alcon Inc)

Anecortave acetate

Steroid (works by slowing or stopping growth of new blood vessels)

Phase III

None

Glaucoma

Wet AMD

15mg every 6 months

Intravitreal (in the eye) injection

2011

Phase 3 (On 9-2007, Retaane received an approvable letter from the FDA. In the letter, the FDA requested an additional clinical trial to demonstrate efficacy prior to final approval. Additional clinical trials are pending.

Verteporfin --Visudyne

(Novartis)

Verteporfin & ranibizumab

Photosensitizing agent/ Monoclonal antibody

ophthalmologic agent

Phase II/III

Wet AMD

Combination treatment wet AMD

Intravitreal injection

2010-2011

Ophthalmologists are starting to explore the possibility of using combination therapy to obtain better and longer lasting results. Many of these studies are physician initiated vs. Pharma sponsored.

Zinthionein (Pipex)

Zinc-monocysteine

Not yet determined

Phase III

None

Dry AMD

25 mg twice a day

Oral

AL-8309B

(Alcon Research)

Phase III

None

AMD

1.75% or 1%

1 drop BID

Ophthalmic solution

Ongoing but not recruiting participants

Prostavasin

Alprostadil

ProstaglandinE1

Phase III

None

Dry AMD

60 mcg daily

Intravenous

Study terminated 4/16/2010

Copaxone

Glatiramer acetate

Immunomodulatory agent

Phase II/III

Multiple sclerosis

Dry AMD

Subcutaneous

Studies currently recruiting

RAD001

(Novartis)

Everolimus

mTOR inhibitor

Phase II

None

Neovascular AMD

Oral

Study terminated 1/31/2011, reason not given

(GlaxoSmithKline)

Pazopanib

VEGFR tyrosine kinase inhibitor

Phase II

None

Neovascular AMD

5 mg/mL TID or QID

10mg/mL BID or TID or QID

Eye drops

The study is currently recruiting participants

AMD = age-related macular degeneration; BID = twice a day; CNV = Choroidal neovascularization of the retina; QID = 4 times a day; TID = 3 times a day; VEGF = vascular endothelial growth factor.

Adapted from references 16-23.

Mr. Allinson is chief executive officer and chief clinical officer of Therigy, LLC.

References

1. National Eye Institute. www.nei.nih.gov/.

2. US Centers for Disease. www.CDC.gov/. Accessed February 2011.

3. Web MD Internet Web site. www.Web MD.com/. Accessed February 2011.

4. Coleman A. Eye-related Medicare costs for patients with age related macular degeneration from 1995-1999. Ophthalmology. 2008; 115:18-25.

5. Gupta O et al. Age related macular degeneration: the costs to society and the patient. Current Opinion in Ophthalmology. 2007;18:201-205.

6. Brown G et al. Pharmacoeconomics and macular degeneration. Curr Opin Ophthalmol. 2007;18:206-211.

7. Rein D et al. The economic burden of major adult visual disorders in the United States. Arch Ophthalmol. 2006;124:1754-1760.

8. Prevent Blindness America. The economic impact of vision problems: the toll of major adult eye disorders, visual impairment and blindness on the U.S. economy. www.preventblindness.org/research/Impact_of_Vision_Problems.pdf. Published 2007.

9. Macular degeneration. Macular degeneration research fact sheet. January 2008.

10. US Department of Health and Human Services. Age related macular degeneration- what you should know. www.nei.nih.gov/health/maculardegen/nei_wysk_amd.PDF.

11. Gupta O et al. Age related macular degeneration: the costs to society and the patient. Current Opinion in Ophthalmology. 2007;18:201-205.

12. Brown MM, Brown GC, Stein JD, et al. Age-related macular degeneration: economic burden and value-based medicine analysis. Can J Ophthalmol. 2005;40:277-287.

13. Frick K et al. Direct costs of blindness experienced by patients enrolled in managed care. Ophthalmology. 2008;115:11-17.

14. US Patent and Trademark Office. www.Uspto.gov. Accessed February 2011.

15. Package insert. Accessed February 2011.

16. Biopharm Insight database. Accessed July 25, 2008.

17. US Food and Drug Administration Web site. www.FDA/gov. Accessed February 2011.

18. CenterWatch Clinical Trials Listing Service. www.Centerwatch.com. Accessed February 2011.

19. US Clinical Trials Web site. www.clinicalTrials.gov. Accessed February 7, 2011.

20. Clinical Pharmacology online. www.clinicalpharmacology-ip.com.lp.hscl.ufl.edu/default.aspx. Accessed 11/01/10

21. Formulary Journal Staff. Bevasiranib trial for wet-AMD discontinued. Formulary. March 12, 2009. http://formularyjournal.modernmedicine.com/formulary/In the Pipeline/Bevasiranib-trial-for-wet-AMD-discontinued/ArticleStandard/Article/detail/586362.Accessed November 1, 2010.

22. Macular degeneration: drug pipeline analysis and market forecasts to 2016: new market analysis released. Business. 2010-04-08 14:51:02. www.pr-inside.com/macular-degeneration-drug-pipeline-analysis-r1820893.htm. Accessed 11/02/10.

23. Bayer, Regeneron wet AMD drug shows promise. Contract Pharma. www.contractpharma.com/news/2010/11/22/bayer%2c_regeneron_wet_amd_drug_shows_promise. Published November 22, 2010. Accessed February 7, 2011.