Marianne:

I've reviewed this issue both within the scope of my work in oncology, and in the general clinical development environment, so I give you below my perspective and a summary of where things stands:

SQUALAMINE

Squalamine lactate is an water-soluble antiangiogenic/anti-VEGF compound derived from the internal organs of dogfish, Squalus acanthias that belongs to the aminosterol class of drugs. Squalamine blocks the action of VEGF and integrin expression when bound to calmodulin, thereby preventing angiogenesis and thus representing a naturally-derived angiogenesis inhibitor. An early phase I/II clinical trial [1] in patients with neovascular AMD and showed vision stability reported positive results in 26% of patients.

Squalamine also has demonstrated significant bactericidal and fungicidal effects and also enhances the bactericidal effects when used in combination with standard antibiotics [2,3], and besides these effects in age-related macular degeneration (AMD, it appears to have had some benefit in certain cancers like NSCLC and melanoma.

WHERE CLINICAL DEVELOPMENT STANDS TODAY

However, the intravenous formula of the drug was terminated in 2007 by Genaera because of financial and subject-recruitment issues, and is no longer in clinical development for AMD [4,5].

The squalamine project was then acquired by Ohr Pharmaceutical, which continues the development of squalamine in a topical eye drop formulation. In 2012, Ohr was awarded Fast Track designation by the U.S. FDA to further develop its Squalamine Eye Drop product for the potential treatment of wet AMD, and a randomized clinical trial was launched in 2012 [6] evaluating the efficacy and safety of topical squalamine lactate for the treatment of neovascular AMD, currently recruiting patients [7].

The most recent development is that on August 20, 2013, Ohr announced the initiation of an investigator-sponsored trial (Study OHR-004) to evaluate the safety and effectiveness of Squalamine Eye Drops for the treatment of macular edema (i.e., a swelling of, or accumulation of fluid in, the macula), secondary to retinal vein occlusion (positive but highly preliminary findings were announced at the 37th Annual Macula Society Meeting this February 2014, solely on a single patient so far) [8].

To me given my research on squalamine to date, the overwhelming appeal of topical squalamine is the ability for the patient to self-administer eye drops to treat wet AMD, which is vastly less invasive and may even be more effective than the current standard of care involving regular physician-administered injections of Lucentis, Avastin, or Eylea directly into the eye.

A WARNING ON NON-PRESCRIPTION ORAL FORMULATIONS

On caution I should note however: many companies (like Nu-Gen Nutrition with its Squalamax product) are marketing oral - not topical and not injectable - squalamine as an over-the-counter (OTC) natural aid to support the immune system, or as an antibiotic, or for other claimed benefits, but I must note that it remains undemonstrated if oral squalamine has similar effects to topical or injectable/systemic forms, and there is insufficient reliable information available about the safety or efficacy of oral squalamine [9]. Therefore such use before further robust studies confirming the safety and efficacy of such oral formulations is premature and unwarranted.

REFERENCES

1. Garcia CA, Quiroz‐Mercado H, Uwaydat S, et al. A phase I/II trial of intravenous squalamine lactate for treatment of choroidal neovascularization in age related macular degeneration (ARMD). Invest Ophthalmol Vis Sci 2004;45:E‐Abstract 2362.

2. Lavigne JP, Brunel JM, Chevalier J, Pages JM. Squalamine, an original chemosensitizer to combat antibiotic-resistant gram-negative bacteria. J Antimicrob Chemother. Apr 2010;65(4):799-801.

3. Salmi C, Loncle C, Vidal N, et al. Squalamine: an appropriate strategy against the emergence of multidrug resistant gram-negative bacteria?PLoS One. 2008;3(7):e2765.

4. Emerson MV, Lauer AK. Current and emerging therapies for the treatment of age-related macular degeneration. Clin Ophthalmol 2008; 2(2): 377–388.

5. Bansal R, Gupta A. What is New in the Management of Age-Related Macular Degeneration?

JIMSA July - September 2010 Vol. 23 No. 3 169.

6. Efficacy and Safety of Squalamine Lactate Eye Drops in Subjects With Neovascular (Wet) Age-related Macular Degeneration (AMD). Clinical Trial NCT01678963.

7. Ohr Pharmaceutical Inc., Efficacy and Safety of Squalamine Lactate Eye Drops in Subjects with Neovascular (Wet) Age-Related Macular Degeneration (AMD), National Library of Medicine (US), Bethesda, Md, USA, http://clinicaltrials.gov/ct2/show/NCT01678963.

8. Positive Case Report on Ohr Pharmaceutical's Squalamine Presented at the 37th Annual Macula Society Meeting. Topical Treatment With Squalamine Resulted in Regression of Abnormal Blood Vessels in a Patient With Proliferative Diabetic Retinopathy. Ohr Pharmaceutical Inc. Press Release. 20 February 2014. At: http://www.ohrpharmaceutical.com/media-center/press-releases/detail/124/positive-case-report-on-ohr-pharmaceuticals-squalamine.

9. SQUALAMINE. Natural Medicines Comprehensive Database. At: http://naturaldatabase.therapeuticresearch.com/nd/PrintVersion.aspx?id=751&AspxAutoDetectCookieSupport=1.

Dear Prof. Kaniklidis,

Thank you very much for your comprehensive review on the matter.

Wishing you continued successful and fruitful work,

Sincerely yours,

Prof. Marianne Shahsuvaryan