Following FDA approval of Novartis AG's VEGF-A inhibitor, Beovu (brolucizumab), in wet age-related macular degeneration (AMD) earlier this month, speculation immediately started on how much market share that new therapeutic will capture at the expense of Regeneron Pharmaceutical Inc.'s blockbuster drug, Eylea (aflibercept), the VEGF trap that now spans several ophthalmic disease indications since its original approval for treating wet AMD in November 2011.
The two drugs work by the same essential mechanism, blocking the formation of new blood vessels during the neovascular or advanced stage of wet AMD, which can lead to rapid loss of central vision. Beovu gained FDA approval on the basis of two phase III trials, Hawk and Harrier, in which it attained the primary endpoint of noninferiority vs. Eylea in mean change in best corrected visual acuity from baseline at week 48 of each study. In each study, more than half of the patients on Beovu were maintained on a three-month dosing interval. (See BioWorld, Oct. 9, 2019.)
That dosing schedule improves upon its currently marketed wet AMD drug, Lucentis (ranibizumab), which the Swiss pharm markets worldwide except in the U.S., where it is sold by Roche Holding AG.
While all of those anti-VEGF therapies are effective in helping to prevent central vision loss, their mode of administration, by intravitreal injections, often results in patients discontinuing treatment. That is why new generation medicines that are coming to market or are in late-stage development are being designed for longer treatment intervals that will improve patient compliance.
For example, Roche and Genentech have initiated two global phase III trials to investigate the bispecific molecule faricimab, which is designed to bind to and inactivate angiopoietin-2 and VEGF-A. The companies have said they believe that mode of action may lead to sustained efficacy at longer treatment intervals.
Allergan plc and Molecular Partners AG are also working on a longer treatment interval drug, abicipar. At the recent American Academy of Ophthalmology (AAO) meeting, the companies presented two-year data from the CEDAR and SEQUOIA phase III studies of abicipar in patients with wet AMD. They reported that in the second year of those studies, four injections resulted in the maintenance of visual gains comparable to monthly ranibizumab treatment.
In September, the FDA accepted a BLA and the EMA validated a marketing authorization application for abicipar pegol. The FDA is expected to take action on the BLA in mid-2020 while the decision from the European Commission is expected in the second half of next year.
One and done
The ultimate treatment for wet AMD would be a "one and done" gene therapy designed to relieve patients from the frequent injections that they have to undergo with the current crop of innovative therapies. While initial studies in the field didn't pan out, the lessons learned are now being applied to new evolving therapies.
Two companies, Menlo Park, Calif.-based Adverum Biotechnologies Inc. and Regenxbio Inc., of Rockville, Md., are in early stage testing of gene therapy products targeting the disease. (See BioWorld, Oct. 9, 2019.)
Adverum's ADVM-022 deploys a proprietary vector capsid (AAV.7m8) carrying an aflibercept coding sequence under the control of an expression cassette that is administered as a single, intravitreal injection. The company reported additional clinical data for the first cohort of patients (n=6) in an ongoing OPTIC phase I trial of ADVM-022 in treatment-experienced patients with wet AMD at the AAO meeting.
In treatment-experienced patients previously requiring frequent anti-VEGF injections to maintain vision, the company said the data continue to demonstrate that the single ADVM-022 injection in that cohort was sufficient to maintain vision, with zero rescue injections required for any of the six patients.
Regenxbio is advancing RGX-314 as a one-time subretinal treatment for wet AMD that includes the NAV AAV8 vector containing a gene encoding for a monoclonal antibody fragment. The expressed protein is designed to neutralize VEGF activity, modifying the pathway for formation of new leaky blood vessels and retinal fluid accumulation.
At the AAO meeting, the company reported interim data from their ongoing dose-escalation phase I/IIa trial of RGX-314 that the company said "further demonstrates the significant reduction in anti-VEGF treatment burden and encouraging improvement or maintenance of effects on vision and retinal thickness in the three higher dose cohorts."
In the study, subjects with severe wet AMD requiring frequent anti-VEGF injections have been treated across five dose cohorts.
The interim update included data as of Oct. 9, for cohorts four and five, which enrolled 12 subjects each, at doses of 1.6x10^11 GC/eye and 2.5x10^11 GC/eye, respectively. All 12 subjects in cohort four reached six months of follow-up, and subjects in cohort five reached five or six months of follow-up as of the data cut-off, with the exception of one subject who discontinued from the study at four months.
Subjects in cohort five on average had a meaningful reduction in anti-VEGF treatment burden, with nine out of 12 (75%) subjects remaining anti-VEGF injection-free as of the data cut-off. Across the 12 subjects, there was a mean of 0.8 injections through five or six months following administration of RGX-314, a reduction of over 80% from the mean annualized injection rate during the 12 months prior to administration of RGX-314. "The notable reduction in anti-VEGF treatments seen after a single administration of the highest dose of RGX-314 in cohort five is particularly encouraging, given the severity of the disease and the high treatment burden for these enrolled subjects prior to administration of RGX-314," noted Steve Pakola, chief medical officer of the company.
In a Jefferies report to investors, analysts noted, "While both programs continue to show activity, the commercial viability remains in question as other competitive programs are in development to extend treatment duration but without the sig[nificant] up-front cost associated with a gene therapy."
Plenty of players...
As the population ages, the large $9 billion-plus and growing wet AMD market continues to attract a significant number of biopharmas hoping to capture a piece of that pie and, as a result, the current product pipeline is full.
In addition to gene therapies, other treatment strategies are in the works, including long-term delivery vehicles that are implanted in the eye and combination treatments with existing approved therapies.
Mount Arlington, N.J.-based Panoptica Inc. is developing PAN-90806, a once-daily topical formulation of a small-molecule anti-VEGF eye drop for the treatment of wet AMD. This month, the company presented top-line results from a phase I/II dose-ranging trial at the Ophthalmology Innovation Summit in San Francisco.
More than half of participants receiving once-daily topical PAN-90806 ophthalmic suspension for 12 weeks completed the study without needing rescue with anti-VEGF intraocular injection medication. Of those patients, 88% experienced either clinical improvement or stability of their disease, the company noted.
The company said it is now searching for strategic partners in an effort "to support the rapid development, registration and commercialization of PAN-90806."
It has retained JMP Securities to represent the company in merger and acquisition discussions and to manage ongoing and future dialogue with potential strategic partners.
...and clinical activity
Also this month, Kodiak Sciences Inc. reported the first patients have been treated in a phase II DAZZLE trial of anti-VEGF antibody biopolymer conjugate KSI-301 in patients with treatment-naïve wet AMD. At least 368 patients worldwide are expected to enroll in the study. (See BioWorld, Oct. 14, 2019.)
In the experimental arm, 5 mg of KSI-301 will be administered by intravitreal injection into the eye at 12-, 16- and 20-week intervals. In the active comparator arm, 2 mg of aflibercept will be administered by intravitreal injection into the eye once every four weeks for three consecutive months, followed by an administration once every eight weeks. The primary outcome measure is the mean change in best corrected visual acuity (BCVA).
Melbourne, Australia-based Opthea Ltd. reported, in August, positive phase IIb results demonstrating that OPT-302 combination therapy met the primary endpoint of superiority in mean visual acuity gain at 24 weeks compared to Lucentis monotherapy in treatment-naïve patients with wet AMD. OPT-302 is a soluble form of the VEGF receptor 3 or "trap" molecule that blocks the activity of VEGF-C and VEGF-D. (See BioWorld, Aug. 8, 2019.)
It followed up with additional data analyses from the completed 366-patient study of OPT-302 with ranibizumab compared to ranibizumab alone at the Ophthalmology Innovation Summit. New clinical data included prespecified subgroup and exploratory analyses showing additive benefit of OPT-302 combination therapy in patients with wet AMD lesions. The additional data, the company said, support the recent reporting of superiority with OPT-302 combination therapy over ranibizumab in mean changes in BCVA from baseline to week 24 in treatment-naïve patients.