With much anticipation, Advanced Cell Technology (OTC-ACTC) recently released preliminary results from its highly scrutinized phase I/II clinical trials in Stargardt's macular dystrophy (SMD) and dry-age related macular degeneration (dry-AMD) using human embryonic stem cell-derived Retinal Pigmental Epithelial (hESC-RPE) cells. Both patients, one with SMD and another with dry-AMD, had remarkably improved vision which makes ACTC's commercial future even more appealing considering the recent bow out of competitor Geron (NASDAQ-GERN). Last November, Geron halted its clinical trial using human embryonic stem cell-derived cells in patients with spinal cord injury for financial reasons, not to be confused with a lack of medical promise. Now, ACTC stands and is poised to lead the regenerative medicine movement forward.
Both patients were injected with 50,000 fully differentiated hESC-RPE cells. Since RPE degeneration leads to photoreceptor loss, transplantation of RPE cells could theoretically restore vision (or, at least, slow disease progression by preventing further photoreceptor loss). Essentially, RPE cells maintain the microenvironment where photoreceptors reside by clearing debris, recycling proteins, and transporting molecules. Preclinical studies done in mice revealed a 23% visual improvement in treated mice relative to sham-injected and untreated (Lu et al., 2009). Therefore, it should come as no surprise that both patients had improvements in vision.
Five weeks after surgery, the SMD patient went from seeing hand motions [a 0 letter equivalent on an Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart] to reading five letters. Importantly, this visual improvement was coupled to anatomical evidence demonstrating cell engraftment meaning the cells injected were responsible for the visual improvement as opposed to the placebo effect or co-administration of immunosuppressive drugs. Wisely, the site chosen for injection was predetermined such that the Bruch's membrane was not completely lost to disease (which is lost in advanced atrophic disease) as RPE cells attach to it in order maintain photoreceptor viability. While the dry-AMD patient did not show engraftment, her best-corrected visual acuity went from 21 letters at baseline to 33 letters two weeks later. At week six, she was reading at 28 ETDRS which persisted through postoperative month three meaning the treatment initially improved her vision and ultimately stabilized disease progression. Confounding these incredible results, however, her other eye showed functional improvement too. Now, Dr. Schwartz, the surgeon responsible for the surgery, and colleagues believe her visual improvement was directly due to hESC-RPE treatment. It is important to note, only one eye of each patient was injected leaving concerns as how to conduct a pivotal phase 3 trial for FDA approval. The investigators may to have to perform a sham-injected surgery in one eye and an RPE-injected surgery in the other to confirm the therapeutic potential of hESC-RPE.
Continued monitoring of the cells post surgery revealed no safety concerns as far as abnormal growth or immune rejection. In hindsight, these concerns were addressed in advance of the clinical trials. Preclinical spike-in studies in which mice were injected with 0.01, 0.1, and 1% of embryonic stem cells revealed no tumors. Furthermore, extensive screening was in place such that less than one undifferentiated stem cell could be detected in a pool of a million cells, thus limiting the potential for tumor formation. Therefore, injecting 50,000 RPE cells were well within ACTC's limit of detection. Moreover, the eye is immune-privileged in that it is protected by a blood barrier, hence minimizing the possibility of an immune attack as the cells injected were allogeneic as opposed to being autologous to the recipient. Meaning, the cells used for treatment were not an exact genetic match.
Visual disorders are a $50 billion per year commercial market in the US alone. More than 30 million people worldwide suffer from dry-AMD. When you consider the ongoing clinical trials in the US and Europe, where one SMD patient was recently injected in the United Kingdom, the market potential for embryonic stem cell-derived therapies is incredibly lucrative, especially in treating dry-AMD where there is no currently available effective treatment. In addition, ACTC has been granted orphan drug designation for SMD in the US meaning: 1) 7-10 years of market exclusivity once FDA approved and 2) off-label treatment of dry-AMD patients, a common practice among doctors who treat one unapproved disease (dry-AMD) with an indication for another (in this case, SMD). Ultimately, hESC-RPE treatment has the makings of blockbuster status. At the very least, conversations with big pharma are ongoing, with a joint partnership a strong possibility.
Disclosure: I am long ACTC.OB.