Thursday, January 15, 2015

Oraya IRay Update 3: Oraya Now Operating at Nine European Centers and Partnership with Carl Zeiss Meditec

The last time I checked in on Oraya, in March 2013 (Oraya IRay Update 2: INTREPID Two-year Results Meet Primary Clinical Endpoint - Results in At Least 35% Fewer anti-VEGF Injections), the company had just announced the two-year results of the INTREPID clinical study, showing favorable results in requiring fewer anti-VEGF treatments to treat wet AMD.

With the recent announcement (January 7, 2015) of a collaboration agreement between Oraya and Carl Zeiss Meditec, to provide funding to Oraya over a period of up to two years for the implementation of Oraya's growth strategy, and a report of the three-year INTREPID safety results last September, I decided to publish this update.

First, the three-year INTREPID trial safety results.

The three-year safety results were presented on September 13, 2014, at a EURETINA seminar where physicians also discussed their clinical experiences treating patients with Oraya Therapy.

The three year safety evaluation consisted of detailed image analysis looking for the presence of microvascular changes related to radiotherapy. Although small localized changes were identified by the reading center in a quarter of the patients, they did not significantly affect vision.

Commenting on the INTREPID study, Professor Ian Rennie, Consultant Ophthalmologist and Professor of Ophthalmology and Orthoptics and International Expert in Treatments of Ocular Cancers at Sheffield Teaching Hospitals NHS Foundation Trust said, "Of the cases I reviewed that were identified by the study expert panel as having microvascular changes attributable to radiation, most cases were so subtle that I would consider them clinically insignificant."

The INTREPID study was the first to evaluate the safety and efficacy of Oraya Therapy in conjunction with as-needed anti-VEGF injections for patients with wet AMD, and is the only sham-controlled double-masked trial to assess stereotactic radiotherapy for wet AMD. The study met primary and secondary endpoints and showed that Oraya Therapy significantly reduces the need for anti-VEGF injections while maintaining vision in the presence of a favorable safety profile. A total of 21 sites in five European countries participated in the trial. Two-year results showed that a broadly inclusive cohort of previously treated Wet AMD patients continued to receive the benefits of a 25 % mean reduction in anti-VEGF injections over two years. Additionally, the targeted patient population maintained an impressive 45 % mean reduction in injections through the two-year visit, with stable vision.

In simpler terms, as explained by Oraya President and CEO Jim Taylor, “The INTREPID trial enrolled a broad spectrum of patients, with some diagnosed out to 3 years prior (average ~15-18 months), and including many who's disease process had progressed to central scarring and other related conditions. In this broad cohort, we saw the 25% reduction of injections with equivalent vision outcomes to the controls.”

Further, “In a subset of patients who had active leakage and lesions that had not grown so large as to extend outside the Oraya treatment zone, we saw the far more significant 45% reduction; and some suggestion of potential for positive vision benefit as well. This becomes our "target patient population" for commercial/clinical use, and it is important to note that our research suggests these patients make up 60%-70% of the patient population under wet AMD management in a typical clinic.”

These impressive results coupled with increasing interest from physicians and patients, have led the Heart of England NHS Foundation Trust to become the second NHS center to install the technology. Patient treatment at the Trust was due to commence in October 2014. The Heart of England closely follows the Royal Hallamshire Trust in Sheffield, which began offering this innovative therapy in July 2014. The commercial use of Oraya Therapy has been rapidly expanding in Europe, with the treatment available in a total of eight centers (see note below) across the United Kingdom, Germany and Switzerland. It is covered by insurance in all three countries.

“As we conclude this ground-breaking three-year study of Oraya Therapy, results are showing that treatment can, and is, maintaining patients’ vision while significantly enhancing their quality of life,” said JimTaylor. “This result, coupled with the rapid expansion of the availability of the Oraya Therapy in the UK, and indeed across Europe, makes this a very exciting time for the company.”

(Editor’s Note: As of January 2015, there are now nine centers treating patients; four in the UK, one in Switzerland, and four in Germany. See the company website for additional information.)

On January 7, 2015, Carl Zeiss Meditec AG and Oraya Therapeutics, Inc. (Oraya) jointly announced that the companies had entered into a collaboration agreement under which Carl Zeiss Meditec will provide funding to Oraya over a period of up to two years for the implementation of  Oraya's growth strategy, and in turn receive rights in the company reaching up to a majority stake after two years.

The Oraya Therapy is available commercially in Germany, the UK and Switzerland, and the collaboration is intended to accelerate and expand these initial European market developments. While specific terms of the agreement were not disclosed, the companies noted that Carl Zeiss Meditec will be making a meaningful strategic investment in Oraya, and that further opportunities to leverage the companies' respective technical and market expertise and resources will be reviewed.

In discussing the transaction, Dr. Ludwin Monz, President and CEO of Carl Zeiss Meditec AG, stated, "The current pharmaceutical treatment regimens for wet AMD are exceptionally costly and burdensome, and Oraya's unique therapy offers a significant potential to positively impact the management of this debilitating disease." He went on to add that, "ZEISS has a long tradition of bringing new and innovative technologies to the ophthalmic market, from the earliest slit lamps, to category leading products such as glaucoma field analyzers, Optical Coherence Tomography (OCT) and innovative femtosecond laser platforms. These types of technology innovations, all offering significant provider and patient benefits, are part of the core strategy of Carl Zeiss Meditec AG."

Commenting on the agreement, Jim Taylor, CEO of Oraya, stated, "It is exceptionally rewarding to have the support and validation that are inherent in this commitment by Zeiss, a company universally recognized for its commitment to excellence in science as well as in patient-focused and physician-focused products and innovations. As a result of this collaboration, we have effectively enhanced our potential to positively impact patient outcomes, while significantly reducing the therapy burden for clinicians and providers as well."

In the USA the Oraya IRay is still an investigational device and is not yet available for sale.

Wednesday, January 07, 2015

Iluvien Update 9: Additional Marketing Approvals; A New Ophthalmic Application; and An Interesting Human Interest Story

Since I last wrote about Iluvien back in September (Iluvien Update 8: Alimera Sciences Receives FDA Approval of Iluvien for Treatment of DME), when Alimera Sciences and pSivida announced the FDA approval of Iluvien for treating chronic DME, adding the U.S. to the approvals or pending approvals obtained in seventeen European countries – approved in thirteen and pending approval in an additional four others, the product has become commercially available in the UK and Germany and is scheduled to become available in Portugal shortly.

With the FDA approval, Iluvien should also become commercially available in the U.S. in early 2015.

In a recent news release, Dr. Paul Ashton, President and CEO of pSivida, said, "We continue to be pleased as Iluvien gains additional marketing approvals in Europe. We believe Iluvien’s efficacy and three-year duration make it an attractive treatment option for many DME patients, particularly in the U.S. where the drug has broader labeling."

In addition to the application of Iluvien for the treatment of DME licensed to Alimera, pSivida is independently developing the product for the treatment of posterior uveitis. The FDA recently cleared the company's Investigational New Drug (IND) application to treat posterior uveitis with its injectable, sustained-release micro-insert, permitting pSivida to move directly to two Phase III trials under which it would enroll a total of 300 patients. However, the FDA approval of Iluvien for DME opens up the potential for pSivida to seek FDA approval on Medidur for uveitis with only one Phase III clinical trial, similar to what occurred with Allergan’s Ozurdex and its FDA approvals. The FDA is allowing pSivida to reference much of the data, including the clinical safety data, from the clinical trials of Iluvien for DME previously conducted by Alimera. Under the terms of its collaboration agreement with Alimera, pSivida has joint ownership of, and reference rights to, all clinical data and regulatory filings generated by Alimera, including its New Drug Application (NDA) for DME.

pSivida’s injectable micro-insert (Medidur) to treat posterior uveitis is a tiny tube about the size of an eyelash. It releases the off-patent steroid fluocinolone acetonide at a consistent rate over a period of approximately 36 months. The micro-insert is injected into the back of the eye during an office visit through the use of a fine gauge needle.

And, An Interesting Human Interest Story

What caught my attention, and brought me back to Iluvien (and the company, pSivida, that produces it and licenses it to Alimera Sciences for marketing) was a story that recently appeared in the Kansas City Star:

This is a story about a software engineer from Olathe, Kansas.

David Jiang was in danger of losing vision in his left eye when his eye specialist tracked down the inventor of a tiny eye implant that releases an anti-viral drug.

Jiang was examined recently by Siddhartha Ganguly (left) at the University of Kansas Cancer Center. 

David Jiang (left) says his vision remains slightly blurry but his retina is recovering after receiving the implant.

A year ago, after a routine physical, Jiang got the disturbing news that he had leukemia.

"I was shocked," he said, when his doctor called him with the diagnosis. His life was in danger, the doctor warned him. Jiang had been heading out the door to lunch. He changed his destination to the University of Kansas Cancer Center. The next morning, he started chemotherapy.

But the chemo wasn't doing the job of ridding Jiang's body of his cancerous bone marrow and the abnormal white blood cells they were producing. Doctors decided he needed a bone marrow transplant, a tough and sometimes risky course of treatment. A bone marrow donor was found, and Jiang received the transplant in April.

So, what does this have to do with Jiang's eyesight?

Before cancer patients undergo a bone marrow transplant, they must go through a rigorous course of chemotherapy or radiation to eliminate their own diseased marrow from their bones. The donated marrow is infused into their bloodstream and migrates to their bones, where it grows and begins producing healthy blood cells.

But bone marrow cells are also the source of the body's immune system. Until new marrow can renew patients' immune systems, they're exceedingly vulnerable to all kinds of infections. And as with other kinds of transplants, there's the potential for rejection, which can slow recovery.

When kidneys, livers and other organs are transplanted, the immune system of their new owner may sense them as foreign objects and launch a search and destroy mission. But with bone marrow transplants, rejection comes with a twist. It's the bone marrow itself, the person's new immune system, that sees its new home as the alien and attacks the patient. It's called graft versus host disease.

That's what happened to Jiang. "After the transplant, I was exhausted," he said. "I had one complication after another." There were headaches and stomach pain. To keep his graft versus host reaction in check, Jiang had to take drugs to suppress his immune system.

And that is how his eyesight was put in jeopardy.

Like most adults, Jiang is a carrier of cytomegalovirus, also called CMV. It's scary-sounding, and the virus can be life-threatening. But people with healthy immune systems generally keep it in check and never know they carry it. But in people with compromised immune systems, such as those with AIDS or bone marrow transplants, cytomegalovirus can cause big trouble.

Depending on which organs CMV attacks, it can cause inflammation of the brain, seizures, coma, ulcers in the digestive tract, pneumonia or inflammation of the liver. The virus also can attack the eyes.

For Jiang, it began a painful attack on the retina of his left eye, blurring his vision.

"We needed to stop this virus where it was or it was going to eat away the center of his vision," said Ajay Singh, Jiang's eye specialist at the University of Kansas Hospital. Singh started twice weekly injections of an anti-viral drug (ganciclovir) directly into Jiang's eyeball. The injections were painful and risked causing an infection. Singh couldn't give Jiang an oral version of the drug because it could damage his new bone marrow.

But Singh knew that during the AIDS epidemic, CMV eye infections were so common that a tiny device was created that could be loaded with medication and implanted directly into a patient's eye where it would slowly release the drug. Singh wanted one of these implants for Jiang - his patient was an ideal candidate - but they were nowhere to be found. It turned out that AIDS treatment had advanced so far that people with AIDS no longer were developing CMV eye infections. The implant manufacturer had pulled it off the market about a year or two ago, he found.

Singh was worried: The infection was a millimeter from the center of vision of Jiang's retina. If he didn't get an implant within a month, his vision could be lost. "The odds were stacked against him."

Early in October, Singh started making calls to Singapore, India and Mexico City, searching for an implant. He emailed the CEO of the company that discontinued the device but never received an answer. Eventually, the people Singh was contacting told him of an eye doctor in Kentucky who knew the original inventor of the implant. The Kentucky doctor put the two in touch. And it is here that the inventor-entrepreneur enters the picture.

"Dr. Singh somehow rooted me out," said Paul Ashton, CEO of Massachusetts-based pSivida. While pSivida had licensed its CMV implants to another company, it was still making other drug-dispensing eye implants.

Its newest is the size of an eyelash and can hold enough medication to treat diabetic eye disease for three years. Ashton offered Singh a slightly larger implant, about the size of a grain of rice, that would hold enough of the ganciclovir anti-viral drug.

"It was simply a matter of putting in a different drug," Ashton said. "We were changing the ammunition but keeping the same gun."

Singh recalled Ashton saying: "If you can send me the drug and get approval from the Food and Drug Administration, I will make you the implant." So Ashton went to his laboratory, testing the permeable ends of the tiny tube to be sure they would allow the drug to ooze out at the right speed. "It was a month of many sleepless nights. It was a race against time," Ashton said. "You can't keep injecting someone in the eye. Something bad is going to happen." Singh marveled at the speed with which Ashton's laboratory worked. "It's not like a car engine part" off the shelf, Singh said. "They have to test it. To do it in four weeks is a big deal."

In early November, the implant was ready. Singh called the FDA for emergency approval for the implant. "The FDA responded at lightning speed," he said. "I got an answer in four hours."

On Nov. 5, Singh implanted the device in Jiang's eye at KU Hospital.

"Now his cancer doctors can keep working on getting his bone marrow up and running," Singh said. The implant will continue delivering the drug to Jiang's eye for nine months to a year. "By that time, his immune system can recover and get the virus under control again."

Jiang said his vision is still a bit blurry, but his retina is recovering. Singh has assured him that in a few months, with new prescription glasses, he will be seeing well again. So far, his cancer hasn't returned and his graft versus host disease is well-controlled.

Jiang is grateful to the far-flung team that saved the vision in his left eye. "They all worked together. They worked so well together. I'm so fortunate."

To read more about how the pSivida drug delivery system works, please take a look at my initial writeup of Iluvien: Iluvien and the Future of Ophthalmic Drug Delivery Systems.


Tiny device and lots of teamwork save Olathe leukemia patient's sight, Alan Bailey, The Kansas City Star, January 2, 2015.