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Sustained Release Ocular Bevacizumab for the treatment of wet acute macular degeneration

Periodic Reporting for period 1 - STROBE (Sustained Release Ocular Bevacizumab for the treatment of wet acute macular degeneration)

Reporting period: 2015-05-01 to 2015-10-31

Wet AMD is the leading cause of blindness in those aged 50 and over, symptoms include blurring distortion and loss of central vision which almost always affects quality of life. Lucentis (ranicizumab) is the leading licensed product for the treatment of wet AMD, however the cost implications (£750/injection) has opened the doors for more cost-effect products to be developed. Bevacizumab is currently used off-license for the treatment of wet AMD. Critical Pharmaceuticals Ltd (CPL) intend to develop an intra-oclular delivery of a sustained release microparticle for the treatment of wet AMD. The objective of the study is to:


1. Develop a 3-month sustained release microparticle injectable dosage form using CPL’s novel CriticalMixTM process (supercritical fluid).

2. Draft a target product profile setting out the expected label claims for SR Bevacizumab and secure feedback from key opinion leaders on the expected clinical benefits for the treatment of AMD.

3. Draft a product plan, including plans for pharmaceuticals quality/manufacture, preclinical and clinical safety and efficacy studies, and define a route to market.
CPL SR microparticle formulation development (3-month release)

Microparticles were manufactured using CPLs novel CriticalMixTM process, composed of RG502 (commercially available biodegradable polymer) with a range of release altering excipients such as hyaluronic acid (HA), Poloxamer, PEG and sugars. Microparticles were loaded with 13%w/w bevacizumab and assessed for in vitro release. All formulations had a burst release of 80% within the 1st hour. By the 1-month time-point, bevacizumab release is in the range of 1-5 ng, before a second phase of bevacizumab release is initiated. The second phase of release is associated with the onset of polymer degradation, and the controlled release of bevacizumab from the microparticles. At 3-months, more than 100ng of bevacizumab is being release from the microparticles. Microparticles containing PEG achieved a consistent release of bevacizumab over 3-months (300-500ng from 1-3 months).
Lucentis (ranicizumab) has a Cmax of 0.79-2.90ng/mL and a Cmin of 0.07-0.49ng/mL in vivo. CPL microparticles are significantly above this threshold in vitro. Therefore, with a higher pay-load of bevacizumab, a lower concentration of microparticles could be administered into the eye, potentially achieving a similar or greater therapeutic effect.


Target Product Profile

Having approached key opinion leaders in ophthalmology and wet AMD, populations highlighted as most at risk of acquiring wet AMD included: adults in their late 70s, smokers (3x at risk than other population groups), the ageing population, CFH variant, and those with a genetic risk associated with the disease. There is a lot of research being invested into the treatment for dry and wet AMD, including stem cell research. A long-acting treatment was regarded as a preferred method of treatment for the elderly, particularly for those patients who would find it difficult to regularly attend hospital for treatment.


Pharmacoeconomic model

Applying the NICE model for ranibizumab, has limited value in establishing the cost effectiveness of slow release bevacizumab.
Key findings include:
• previous work for NICE has not included in QALYs the discomfort due to injections,
• inclusion of such discomfort would have minimal impact on QALYs,
• trial evidence suggests that fewer injections are associated with more adverse events.
• small differences in Quality of Life, favoring continuous over discontinuous treatment, were observed in the IVAN trial
• cost savings due to reduced injections were relatively small in the IVAN trial but this may be due to the monitoring required in trial conditions.


Conclusion

Critical Pharmaceuticals successfully encapsulated Avastin® in a biodegradable polymer (50:50 PLGA) using its supercritical Fluid technology, to form a 3-month sustained release microparticle.
Commercial exploitation

Engagin with key opinion leaders in teh ophthalmology field of study, it was highlighted large pharmaceutical companies were already investing large interest in bevacizumab and alternative therapies for wet AMD, with many companies already establishing phase 2 and phase 3 trials for 3-month sustained release dosage forms. It is important to note Intas Pharmaceuticals (India) has already developed and marketed a biosimilar product to Lucentis®, which is 25% cheaper for the patient. Due to the high number of competitors already more advanced down the development pipeline, any commercial exploitation for Critical Pharmaceuticals will be limited. For Critical Pharmaceuticals to become a competitor on the commercial scale, it is in the company’s interest to continue with further R&D to develop a 6-month sustained release product.

Conclusion

Critical Pharmaceuticals successfully encapsulated Avastin® in a biodegradable polymer (50:50 PLGA) using its supercritical Fluid technology, to form a 3-month sustained release microparticle. This study has shown CPL microparticles enable better controlled release of Avastin® over a 3-month period. The next stage involves further formulation development to (1) lower the burst release seen within the first few days of in vitro release and (2) extend release in vivo to 6 months.
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