Hope in sight with Apellis’ pegcetacoplan OAKS/DERBY results for GA

Views & Analysis
leading cause of blindness worldwide

Last month, pharmaphorum spoke with Dr Charles C. Wykoff about the results from Apellis Pharmaceuticals’ OAKS study on intravitreal pegcetacoplan for geographic atrophy (GA), otherwise known as atrophic or dry age-related macular degeneration (AMD), a leading cause of blindness worldwide.

Having presented the data from the 24-month phase 3 trial at the American Academy of Ophthalmology (AAO) annual meeting, Dr Wykoff set aside some time to go into further detail with pharmaphorum about how the results were received, and what glimmer of hope this might hold for patients with GA.

Working against the odds

“As way of background,” he began, “geographic atrophy is an advanced stage of age-related macular degeneration which causes a tremendous amount of blindness. It’s one of the most common causes of blindness across Europe and across the United States, and many developed countries around the world. In that context, there is no treatment today for GA. There’s simply nothing: nothing that works to slow it down, nothing that works to reverse it.”

Bleak prospects, indeed. And yet, the OAKS study, as well as the DERBY study, has illuminated possible hope on the horizon.

“What’s exciting about this entire development programme,” Dr Wykoff continued, “is that pegcetacoplan is positioned possibly to be the first approved therapeutic to slow the progression of geographic atrophy. That’s why there’s a lot of interest around this particular molecule and around this development programme.”

Crucial research for unmet needs and people’s future sight

As the name suggests, AMD is an age-related disease; it becomes more prevalent as we get older. The average age for diagnosis is over the age of 50, and most patients are in their 70s or 80s.

“AMD is the most common cause of blindness by far, in the US, in Europe, in many parts around the world,” Dr Wykoff said. “There are two advanced forms of AMD: the wet form or neovascular form, [for which] there are treatments, there are medicines we inject intravitreally in patients routinely, and we’ve been using those medicines now for 15-plus years, and they’re called anti-VEGF medications, they block the VEGF growth factor [and] are highly effective at controlling the wet form of this disease process.”

“But the other form of advanced AMD,” he went on, “and which is a huge unmet need, I think, is perhaps the largest unmet need […] is that there is no treatment for the advanced dry form of [AMD] and these advanced forms can be concurrent in the same eye – it’s not like the eye gets one or the other, oftentimes at the advanced stage patients can have both the wet and the dry form of AMD.”

The specifics of an exciting prospect

Asked to elucidate the specifics of what the study had found, Dr Wykoff’s positivity over the “large, global clinical trial” was palpable; certainly, he is deeply passionate about his specialist area.

“To dive into specifics, […] OAKS and DERBY were identical trials. They had one slight difference, in that OAKS used microperimetry as an endpoint assessment to evaluate that visual function in a very specific way, whereas DERBY did not. But combined, OAKS and DERBY were two phase 3 trials involving 1,258 patients […] randomised equally to one of three arms essentially: pegcetacoplan 15mg monthly, same drug same dose every other month, or sham treatment through two complete years,” Dr Wykoff said.

Although the primary endpoint was achieved at Year One and presented not long after, this year the trial yielded new data at the Year Two endpoint, the end of the phase 3 clinical trial programme. That data involved functional outcomes, and not just in terms of slowing the atrophy, the area of growth, within the macular.

“So, really,” he continued, “[there are] three major take-homes to talk about: first efficacy, then function, and then safety. From an efficacy perspective, […] through two years the treatment effects of pegcetacoplan were similar between the trials and there were reductions in GA lesion growth – between 16% and 18% with every other month dosing, and 19% to 22% with monthly dosing. All of these statistical comparisons are nominal, but the nominal p-values were highly significant at 0.003 or less.”

Effective reduction in GA lesion growth over time

Dr Wykoff also said: “Maybe the most interesting finding, from an efficacy perspective, was the finding that, when looking at reductions in GA lesion growths over six-month periods – 0-6, 6-12, 12-18, and 18-24 month intervals – there appeared to be an increasing treatment effect of pegcetacoplan over time. This was particularly the case in the last six months, when there were reductions in GA lesion growth of about 24% and 30% with every other month and monthly dosing. So, substantially more than, for example, in the first six months, particularly in DERBY, and there are some fascinating biological hypotheses of why that might be the case.”

Although Dr Wykoff did not elaborate on what those hypotheses were, the fundamental takeaway from his enthusiastic data explanation was clear: pegcetacoplan might be the first effective treatment for geographic atrophy.

“That’s the efficacy data. Then, the second topic to cover is […] the microperimetry data,” Dr Wykoff explained. “Going through the functional data completely here, there were no significant differences across the study arms on the key secondary endpoints: best corrected visual acuity, maximal reading speed, or FRI index. Additionally, there were no differences across the study arms in the prespecified endpoints of mean threshold sensitivity or number of scotomatous points, with microperimetry through month 24.”

The biology of GA and functional preservation

When microperimetry was looked at in “a very specific way”, the benefits of pegcetacoplan treatment to functional preservation could clearly be detected.

“This was a post hoc analysis,” Dr Wykoff explained. “But consistent with the biology of GA expansion – that is, to use microperimetry to look at the visual function around the edges of GA lesions in a patient-specific way. When we do that, we call it a perilesional analysis. There was a signal of preserved function as we slowed GA growth with pegcetacoplan and we saw that both with a reduction in the development of the number of scotomatous points and less loss of mean threshold sensitivity within the last six months.”

Dr Wykoff went on to describe the ophthalmological field as being “quite excited” to see this demonstrable correlation between treatment and outcome in the last six months of the study. However, the question of safety remained a topic yet to be discussed:

“Ocular adverse events were more common in the pegcetacoplan treated arm and this was actually expected, seen at Year One, and was consistent with all other trials in which there’s a sham treatment arm,” Dr Wykoff said. “Some of the patients were receiving sham injections into their eye, whereas the other two thirds of patients were receiving actual intravitreal injections, so, certainly they’re going to experience more symptoms, signs related to the individual injections.”

And what exactly were those adverse events?

“There were four cases of infectious endophthalmitis [an infection of the tissues or fluids inside the eyeball], which was a rate of 0.5% per patient, or 0.034% per injection. Secondly, rates of interocular inflammation were 3.8%, 2.1%, and 0.2% in monthly, other monthly, and sham arms. The majority of these were mild, 66% were mild, 21% were severe, there were no cases of occlusive vasculitis, vasculitis, or retinitis, and the majority of patients - or 77% of patients - actually continued their study-drug treatment or resumed study-drug treatment with no recurrence of inflammation.”

“[Additionally,] in my opinion probably the most important safety angle to consider is rates of wet AMD [age-related macular degeneration] were increased with pegcetacoplan treatment, that is 12.2%, 6.7%, and 3.1% of the monthly, every other month, and sham arms […] This signal is very consistent with Year One data, very consistent with the previous Philly phase 2 trial. There was a fascinating observation with pegcetacoplan treatment with inhibition of C3 and C3b. The biology of this, I think, is teaching us something about this disease processor. We’re still learning what this means from a field perspective.”

Biological teachings and outcomes of the AAO meeting

As Dr Wykoff made clear, there’s no doubt that the OAKS and DERBY data was well-received. After all, GA is almost impossible to treat.

“This is a potentially very large step forward for the field,” he explained. “This drug is not FDA or EMA approved, let’s be very clear, but it’s going to be – the PDUFA date for the FDA is 26th November […] If it is approved, I think the field feels very strongly that this is going to be a very substantial value-add to the field. Something that many, many, many patients around the world could benefit from.”

In fact, since pharmaphorum spoke with Dr Wykoff, the 24-month data has been submitted to the FDA as part of the New Drug Application (NDA) submission, with an extended review period and expected PDUFA target action date now of February 2023. It will be interesting to see what the outcome of that application is.

Risk profiling and concluding remarks

Asked whether there are lifestyle or other biological factors that contribute to the likelihood of developing AMD, Dr Wykoff was keen to expand on risk profiling for the condition.

“The risk profile of developing AMD has been studied for years,” he said, “and more than 50% of a given individual’s risk profile is dependent on their genetics. It’s a complicated genetic risk profile: it involves multiple genes, dozens of genes on 19 different chromosomes, and the most common pathway implicated in that genetic predisposition is actually the complement cascade [which is] part of our innate immune system that helps every human individual, helps their body detect foreign pathogens - such as viruses and bacteria - and get rid of those pathogens before they cause damage to the human.”

“What’s interesting with AMD,” Dr Wykoff continued, “is we think some of these eyes have an increased activity locally within the eye of complement over-activation, so you’re getting a very low-grade increased inflammatory, chronic inflammatory state inside the back of the eye that’s causing breakdown of the ocular tissue, breakdown of the retinal outer layers, and we think that’s why pegcetacoplan is effective here, because [it] inhibits the complement cascade: it blocks C3b, which is an active component that drives the pathway forward, and it also blocks C3 cleavage [C3 is an inert molecule, which essentially leads to complement propagation once the system is activated].”

“So, pegcetacoplan blocks an inflammatory pathway that appears to be central for geopathic genesis based on extensive genetic analysis,” Dr Wykoff concluded.

About the interviewee

Dr WykoffDr Charles C. Wykoff is director of research at Retina Consultants of Texas, chairman of research at Retina Consultants of America, and deputy chair of ophthalmology for the Blanton Eye Institute, Houston Methodist Hospital. He is passionate about translational research, clinical trial design, accelerating drug-development programs, and has published over 250 peer-reviewed manuscripts. He serves on multiple scientific and medical advisory boards, safety monitoring committees, and global steering committees for endeavours spanning the innovative process from early to late-stage developments. His guiding philosophy is to build and strengthen innovative, ethical teams focused on developing new approaches to improving outcomes for blinding diseases.