Inspiration from Nature
The DARPin platform has the AMD and DME treatment burden firmly in its sights – but that’s only the beginning
Michael Stumpp | | Longer Read
In the latter half of the 1990s, medical science and biotech in particular were asking a big question: “What comes after antibodies?”
Antibodies have a strong and successful history and have diverse uses, including drug targeting, diagnostic and research applications. For a time, antibody utility and availability dissuaded people from looking elsewhere – that was until a certain post-doctoral researcher, Patrik Forrer, a co-founder of Molecular Partners, made an enlightening observation: nature also uses a very different class of proteins to achieve the same goal as antibodies. These so-called repeat proteins ultimately provide an immune system that is independent of antibodies. The reality is that immunity to pathogen infections is provided by different mechanisms in plants and animals – and there are surprising similarities and informative differences between the two.
Specific problems – specific solutions
We observed that repeat proteins frequently occur in nature as multi-domain constructs, and therefore have several functions included, which is very different than antibodies. Antibodies have traditionally been designed to target one protein with high specificity, and this has led to the development of targeting drugs. However, the concept of multi-specificity allows a drug to be designed with a number of properties, each one having a “specificity” tailored to its purpose. For example, designing a drug to target a cancer in the brain has to include the chemical properties to allow it to enter the brain specifically (maybe even a particular area or function of the brain), and then to search and find the tumor specifically, before killing the tumor without destroying the neighboring healthy tissue. The challenge was to move from an antibody, which is commonly extremely good at blocking one single pathway, to a multi-purpose molecule, without losing any of the critical specificity required to localize its activity.
Nature is continually faced with complex problems, which it addresses with its armory of proteins. Diseases present as multifaceted problems, where multiple things can go wrong simultaneously. To investigate whether multi-specificity could be designed into new drugs, we focused upon the ankyrin repeat proteins, originally discovered in yeast, and developed the DARPin platform. DARPin (a registered trademark owned by Molecular Partners AG) proteins are genetically engineered, antibody-mimetic proteins. The success achieved within the academic world with DARPin molecules led us to consider how best to bring the platform to clinicians.
We set up Swiss-based biotech company Molecular Partners in 2004 to take early stage candidates through the first clinical trials. Today, Molecular Partners is 130-people strong and still focuses on bringing novel therapeutics to the patient from DARPin technology, obviating the need for complicated and expensive large biologicals. Notably, the platform also benefits from an ability to generate multiple molecules in parallel and to combine these with already-known drugs to improve their efficacy, duration, or targeting.
The eye as a testing ground
The next significant step in our story was inspired by Genentech’s drug Lucentis (ranibizumab) – a humanized anti-VEGF antibody fragment indicated for the treatment of neovascular (wet) AMD, macular edema following retinal vein occlusion, diabetic macular edema (DME), diabetic retinopathy, and myopic choroidal neovascularization. Patients being treated with Lucentis were suddenly regaining sight. However, the frequency of injections was a burden for many patients. And so, we set about designing a DARPin-based compound that had the same therapeutic target but with a longer half-life.
We took the new drug design into the clinic to test whether the drug can last longer in clinical practice. In our first phase I trial, while looking at the safety aspects of the treatment, we were able to determine how long the beneficial effects of the treatment lasted. From this, we were able to test increasing doses using the optimum treatment schedule and investigate patient observations for improvement and duration, correlating these with objective measurements using OCT. The study was a success, not only in demonstrating safety but also determining that the effects of the drug could last beyond a three-month period.
Next, Allergan, the oldest company specializing in ophthalmic solutions, became interested in our work. Allergan had a very ambitious long-term plan to become leaders in the field of retinal diseases – and therefore represented an ideal partner that was able to take the new treatment to the marketplace. Allergan performed the design of the subsequent phase II trial, which comprised three parts: i) a traditional study to address efficacy and ii) an investigation into how much could be achieved with a single dose and iii) how much could be achieved with three loading doses. The trial results demonstrated that a loaded dose every three months compared favorably with monthly dosing of Lucentis, potentially reducing the time a patient would need to spend in clinic and the number of injections received. These results informed the design of the phase III study (see sidebar: “Shaking the AMD Tree”), where Allergan assessed safety and efficacy of 8-week and 12-week treatment regimens compared with monthly ranibizumab in treatment-naïve patients with nAMD, generating the data that allowed the first submission to the FDA for Market Authorization (MA). Two parallel, identical phase III studies, called CEDAR and SEQUOIA were performed and enrolled a total of 1800 patients around the world. Vision increases and the reduction of retinal thickness were the key outcomes. In brief, abicipar at quarterly dosing intervals turned out to be non-inferior compared to standard of care, ranibizumab, given monthly.
All of these studies focused upon AMD. However, a parallel track investigated use in DME, particularly in the familial or diabetic origin of the disease. The results of these studies have now shown that patients respond to loading doses followed by quarterly injections as well as to the monthly injections currently required for Lucentis.
What’s next for the DARPin platform?
We are now waiting for the FDA to grant an MA, and we are continually supplying additional data to assist with this process. Allergan is continuing to work on future clinical trials to include DME. Once there is an MA in place, we hope the drug will be brought back to the EU and begin the process of reimbursement negotiations. Hopefully, we will see a drug on the market in 2020. Allergan will drive the commercialization of the product, extending to other markets, including Japan. I think it’s important to note that i) the drug will be the first anti-VEGF therapy that can be administered quarterly to every patient and, as such, could become a leader in the field, and ii) it is also relatively easy to manufacture. These two points together make it a promising product for Allergan.
Having proved its clinical application in AMD, the future potential of the platform is very exciting. Because the platform does not generate antibodies, but instead smaller and simpler proteins with similar activities to antibodies, we can more rapidly design other multi-purpose drugs. We can certainly design monotherapies, but the really exciting aspect of the technology is the multi-specificity we can build into the molecules. And that is the direction we now want to take Molecular Partners for other drugs and indications, primarily in oncology. Furthermore, DARPin applications outside oncology can be pursued, mainly in partnership with other companies or academic groups.
How does the DARPin technology work?
DARPin proteins are genetically engineered antibody mimetic proteins with binding surfaces. DARPin molecules are relatively small in size, with a molecular weight of around 15 kilodaltons. To put things into perspective – this is approximately one tenth of the size of a conventional IgG antibody, or one half of the size of an antibody fragment (scFv) – the smallest antibody fragment currently approved for therapeutic use.
DARPin proteins also have higher binding affinity against the desired target molecules than antibodies. Their small size affords them greater tissue penetration and their higher binding affinity in the picomolar range means that they are active at low concentrations.
The stability of DARPin molecules is also very high, making them ideal for drug development. The DARPin complexes that are formed are typically cleared by the kidney and removed rapidly from the circulation; however, their half-life in the eye has been prolonged by fusion to polyethylene glycol (PEG), to maximize the biological effect. They exhibit high specificity and have high affinity to the target and so represent an ideal platform for macular degeneration treatment.
Shaking the AMD Tree: what have the clinical trials shown?
Abicipar was studied in two identical phase III multicenter randomized clinical trials, CEDAR and SEQUOIA, which compared the safety and efficacy of abicipar with ranibizumab, in treating exudative AMD. The primary endpoint of the trials was stable vision (loss of fewer than 15 letters) at one year. The secondary endpoints were mean change from baseline in ETDRS vision, mean change from baseline in central retinal thickness on OCT, and the proportion of patients who gain three or more lines of vision. The studies ran through two years.
Both phase III trials together enrolled around 2,000 eyes of 2,000 patients. The patients were randomized to receive abicipar every eight weeks, abicipar every 12 weeks or ranibizumab every month.
Overall the studies met their primary endpoint: at week 52, abicipar (given every eight weeks or every 12 weeks) was non-inferior to monthly ranibizumab. The mean change in visual acuity between the three groups was similar (between 5.6-8.5 letters). The mean change in central retinal thickness was also similar between the groups. However, the incidence of intraocular inflammation was higher in patients treated with abicipar, than in the ranibizumab group. In the second year of the study, the incidence of intraocular inflammation was comparable in all groups.
We have seen in the past that biologics benefit from manufacturing improvements over time, which can lead to decreases in side effects, such as inflammation. As a result of a modified manufacturing process of the DARPin compound, in the most recent, MAPLE study, the inflammation rate was lower than in the previous two studies. We expect more information in the future on these cases, but the improved safety profile with the refined process is very encouraging.
The studies have shown that abicipar is effective when given quarterly for the treatment of exudative AMD. This dosing schedule could greatly decrease the treatment burden for patients with exudative AMD.