Clinical trials set to begin for LHON treatment

Most patients have gone blind from Leber’s hereditary optic neuropathy.

Jerome Sherman

Theodor Leber, if he were alive today, would be both proud and pleased – proud that an optic neuropathy he first described 150 years ago bears his name (Leber’s hereditary optic neuropathy) and pleased that finally an effective treatment to prevent the blindness from this inherited disorder appears to be on the horizon.

It was in 1978 that I first helplessly watched a 17-year-old Greek man go blind from Leber’s hereditary optic neuropathy (LHON). Over the past 3 decades I have seen this first patient followed by dozens of others, mostly males but some females, in the U.S., Greece and Brazil. Some were members of the same family. Many, though not all, faced the same devastating outcome: virtually total blindness.

However, things may be changing. In May, just 1 day after I diagnosed a patient with LHON, he was on a plane to Los Angeles to see my colleague, Alfredo Sadun, MD, PhD, a highly regarded neuro ophthalmologist at Doheny Eye Institute, University of Southern California — Keck School of Medicine. We have reason to hope.

FDA clinical trial

Dr. Sadun is the principal investigator of a clinical trial to treat patients with EPI-743 who have an identifiable LHON mitochondrial mutation and who have recently converted from a carrier state to the acute onset of the characteristic optic neuropathy. According to Guy Miller, MD, PhD, CEO of Edison Pharmaceuticals, EPI-743 is an experimental therapeutic agent being developed for inherited respiratory chain diseases of the mitochondria, including LHON.

Typical optic disc appearance in LHON. A 15-year-old male with a family history of LHON (mt 11778) presented with no symptoms in April 2007. He was being monitored twice yearly. His retinal nerve fiber layer (RNFL) was demonstrated to be thicker than previously in his right eye, signifying early conversion. (A RNFL that thickens more than 10 µ strongly suggests conversion.) One month later, his vision began dropping. By August, his disc was notably pale temporally and his visual acuity had dropped to below 20/400. Images: Sherman J

Over the last year, Dr. Sadun and an international investigator group, in collaboration with Edison Pharmaceuticals, obtained U.S. Food and Drug Administration and University of Southern California Investigative Review Board approval to evaluate EPI-743 in a limited number of LHON patients actively losing vision.

A manuscript entitled “EPI-743 alters the clinical course of the mitochondrial disease Leber’s hereditary optic neuropathy” has recently been submitted for publication. It documents the results of the first five patients with LHON treated with EPI-743. All five patients responded positively to treatment, and two recovered near normal vision.

Data obtained from these trials have served to guide the design of prospective trials for acute converting and chronic LHON patients. These trials have been reviewed and approved by the FDA and were anticipated to commence in July.

My patient who recently converted is a 27-year-old male with the most common of the LHON mutations, mt 11778. He has been treated with EPI-743 for less than 1 month. He is the eighth patient treated with EPI-743, and at this point it appears the drug has prevented further vision loss. We are waiting to see if, like some others, he experiences reversal of disease progression.

My patient is lucky for several reasons. First, I obtained confirmation of his genetic defect 2 decades earlier. When he began converting, the required genetic confirmation was already completed, and this meant he could be promptly treated. Second, although the patient had acute onset of blurred vision dating back several weeks, when I saw him he was still in the early stages of conversion. In addition, treatment was initiated prior to any documented loss of ganglion cells (i.e., the spectral domain ocular coherence tomography ganglion cell complex was normal).

How to diagnose LHON

• It is actually quite simple to diagnose LHON, but first you must consider it.
• Is your patient about 25 years of age, male and complaining of sudden vision loss in one eye?
• Does he have a hyperemic disc with small corkscrew-type vessels in the symptomatic eye?
• Does he have a family history of optic nerve blindness?
• Does your patient also demonstrate a central scotoma?
• If so, he may well have LHON. There are other considerations that need your careful attention.

While males are five times more likely to experience LHON, it does occur in females. And while the majority of patients are young (between 18 years and 30 years old) at the time of vision loss, the disease can affect patients ranging from 4 years to 64 years. A few may not have the characteristic disc appearance that has been described as peripapillary telangiectatic microangiopathy. Some are in families with a history and genetic confirmation of LHON – the largest known pedigree is in Colatina, Brazil – but others present without an established family history.

Now that EPI-743 clinical trials are underway, a timely and correct diagnosis of LHON becomes all the more important. If your asymptomatic patient has slightly unusual discs and a family history of optic nerve disease, it makes sense to obtain genetic analysis and possible confirmation of a LHON mutation prior to vision loss. If you have a patient with longstanding optic nerve atrophy known to be due to LHON, your patient should advise all at-risk family members of the diagnosis and the clinical trial. All those at risk should be informed that smoking and drinking increases the risk.

Typical RNFL findings in LHON. A 20-year-old male in a different family presented in May 2008 with reduced vision in his right eye for at least several weeks. Genetic analysis confirmed LHON (also with the 11778 pt mutation). The RNFL measured with GDx (Carl Zeiss Meditec, Dublin, Calif.) was quite thick initially and remained that way for about a month. Note the first three scans during May and June 2008. As his visual acuity dropped to below 20/400 and his fields worsened, he lost most of his RNFL. The GDx highlighted in green was taken 25 months later. Note the profound drop in the thickness of the RNFL. At first presentation, the NFI (nerve fiber indicator) was the lowest possible, 2 (meaning very thick), and 25 months later it was the highest possible, -98(interpreted as extremely thin).

Patients at risk are those with a maternal inheritance pattern of optic nerve atrophy. In other words, LHON is only passed on to offspring of a female who has the genetic mutation. Men develop the disease far more often than females, but never transmit it to their children.

Are you unsure of the diagnosis? Get an opinion from a retinal specialist or a neuro ophthalmologist or email me the disc images with the clinical profile (j.sherman@sunyopt.edu). I am working closely with Carlos Filipe Chicani, MD, PhD, who is coordinating the clinical trials at University of Southern California and in Brazil. Genetic testing can be obtained through Athena Labs in Boston.

The need for detailed clinical science: Brazil and LHON

I first visited Colatina, Brazil, nearly a decade ago, traveling with dozens of other clinical and basic science researchers from Italy, the U.S. and Brazil to study an extended family with LHON. This work was funded by the International Foundation for Optic Nerve Disease (IFOND), and these studies have proven invaluable as we now embark on an era of a potential treatment.

I was struck by the scores of adorable, happy children that we were studying from the extended LHON family – oblivious to the reason for our presence. All I could think was that we were documenting those at risk of blindness and helpless to change their fate.

This pedigree is now the world’s best documented LHON family, and the natural history in this family is known and predictable. Can EPI-743 alter the course of these patients’ disease? Another clinical trial that is approved by the Brazilian counterpart to the FDA will begin shortly and should answer this question.

Resources:

• Doheny Eye Institute: Clinical trial coordinator, Carlos Filipe Chicani, MD, PhD, cfchicani@gmail.com.
• Edison Pharmaceuticals: www.edisonpharma.com.
• International Foundation for Optic Nerve Disease: http://www.ifond.org/.
• U.S. Food and Drug Administration: www.clinicaltrials.gov.

• Jerome Sherman, OD, FAAO, a member of the Editorial Board of Primary Care Optometry News, is the Distinguished Teaching Professor at the State University of New York and in private practice at the Eye Institute and Laser Center. He is a founding member of IFOND and is on the scientific advisory board. He can be reached at SUNY College of Optometry, 33 West 42nd St., New York, NY 10036; (212) 938-5862; fax: (212) 780-4980; j.sherman@sunyopt.edu.
• Disclosure: Dr. Sherman has no direct financial interest in any products mentioned in this article, nor is he a paid consultant for any companies mentioned.