John Orloff and Brian Goff spoke with BioSpace about Alexion and new trends and developments the company is reporting.
Alexion Pharmaceuticals is a company focused on ultra-rare diseases, although it is working on a shift into rare diseases. This may sound like something of a minor shift, but it represents developing drugs for more diseases with larger patient populations. The company’s success has been built primarily on its Soliris (eculizumab), a complement inhibitor. The drug has been approved for paroxysmal nocturnal hemoglobinuria (PNH), atypical Hemolytic Uremic Syndrome (aHUS) and for generalized Myasthenia Gravis (gMG).
Soliris, as well as the company’s next-generation complement inhibitor, Ultomiris, underline the company’s expertise in complement-related diseases. The complement system is part of the immune system made up of about 30 different proteins. As such it plays a role in numerous diseases at some level, and alone in several diseases, including PNH, aHUS and others.
John Orloff, Alexion’s executive vice president and Head of Research and Development, and Brian Goff, executive vice president and Chief Commercial Officer, spoke with BioSpace about Alexion and new trends and developments the company is reporting.
One piece of news was Alexion presented an abstract regarding a Phase III clinical trial of Soliris in gMG at the recent American Academy of Neurology Annual Meeting held in Philadelphia. Myasthenia gravis is a chronic autoimmune neuromuscular disease resulting in weakness in the skeletal muscles. The muscles most affected control eye and eyelid movement, facial expression, chewing, talking and swallowing. Muscles that control breathing, and neck and limb movements may also be affected.
Goff told BioSpace, “The storyline here is that Soliris was approved for gMG in October 2017 in the U.S. That was based on the pivotal Phase III trial, which was the first FDA approval in more than 60 years in gMG. The concept is a totally different way of treating these patients with complement inhibition. Historically, and to this day, many patients are treated with continuous cycles of immunosuppressant therapy (IST). That’s a different way of treating the disease. Soliris goes to the core mechanisms of complement, the key core of the disease.”
Brian Goff, executive vice president and Chief Commercial Officer of Alexion.
The current trial evaluated the drug in 117 adults with gMG who were on IST who had completed the REGAIN clinical trial, a 6-month, randomized trial of Soliris. During REGAIN, changes in concomitant myasthenia gravis therapies weren’t permitted. But during the open-label expansion (OLE) study, patients received Soliris every two weeks after a 4-week blinded induction phase. Changes to the MG therapies, including ISTs, were at the investigator’s discretion, but weren’t required. Goff notes that they were looking to answer two questions. First, can patients sustain the durability of clinical effect. “More and more we’re seeing that the answer is yes.”
The second question is, in patients receiving IST, if they take Soliris, can they reduce or eliminate IST. And the answer, Goff says, is “yes, there is a cohort of patients who we do believe can reduce the level of IST, which creates a treatment sustainability option for those patients as well.”
The other big news coming out of Alexion was the Phase III PREVENT trial of Soliris in patients with Neuromyelitis Optica Spectrum Disorder (NMOSD). NMOSD is a rare autoimmune, inflammatory disease of the central nervous system (CNS). It is characterized by sudden and unpredictable relapses (attacks). Each relapse results in further disabilities, including potential blindness, paralysis and sometimes early death. Uncontrolled complement activation triggered by anti-AQP4 autoantibodies is a major mechanism of the disease.
Alexion also presented results from the PREVENT trial at the AAN meeting and also published results in the New England Journal of Medicine.
NMOSD, Orloff explains, “was for some time confused with multiple sclerosis (MS), until it was clear it was a different disease that presented like MS. It can be more severe. It typically occurs in women in their 20s and 30s, with 30s being more common. It was previously treated with MS therapies, but not effectively.”
John Orloff, executive vice president and Head of Research and Development at Alexion.
The PREVENT trial was conducted in 70 sites in 18 countries to evaluate the efficacy and safety of Soliris compared to placebo in patients with anti-aquaporin-4 (AQP4) autoantibody-positive NMOSD. There were 143 adults who were randomized 2:1 to Soliris and placebo cohorts. Patients were allowed to receive stable maintenance doses of ISTs to prevent relapse. About 25% did not receive ISTs during the trial.
Orloff said, “This was a little different than other trials, where there’s a defined period, say 6 to 12 months. In this trial, patients contributed varying amounts of time to the analysis because there was time between events. That meant we could continue treating and following patients until we hit a predefined number of relapses based on the anticipated reduction of the risk. Once it reached its target number of adjudicated relapses, we wound it down and found a 94% reduction in relapse with 98% relapse-free in the treatment group on top of standard of care IST. About 75% were on IST and we found consistent results across all groups.”
Soliris is currently being reviewed by the FDA for this indication with a PDUFA action date of June 28, 2019. It is also being reviewed by the European Medicines Agency (EMA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).
Although rare diseases and ultra-rare diseases are defined somewhat differently from country to country, in the U.S. a disease is defined as “rare” if it affects fewer than 200,000 people, or about 620 million per million of population. Europe defines it as affecting fewer than 5 people per 10,000 of the population, or about 500 per million.
Ultra-rare, however, is typically defined as affecting one patient per 50,000 people, or fewer than 20 patients per million of population. Most ultra-rare diseases actually affect far fewer, as low as one per million or less.
Although still committed to treatments for ultra-rare diseases, Alexion is marking a shift to include rare diseases, which is how gMG is classified. Goff notes that since Soliris launched about 18 months ago for gMG, they have now successfully treated over 1,000 gMG patients. “For us to have that patient volume in that time period is a good marker in our movement into rare diseases.
Orloff agrees, pointing out that there are about 60,000 to 80,000 patients with gMG in the U.S., compared to PNH, the first Soliris indication, which affects about 1 to 1.5 people per million of the population.
The company isn’t content to just rely on Soliris. It has a follow-up drug, Ultomiris, which has also been approved for PNH. Orloff says, “there are some distinct advantages over Soliris. First, extended dosing from two weeks to eight weeks. Think of the number of infusions, 25 per year to six or seven. That has quite a dramatic impact on quality of life.”
As such, they are also evaluating Ultomiris in other indications, including aHUS, gMG, and NMOSD. The company also has Strensiq, an enzyme replacement therapy for the treatment of perinatal/infantile- and juvenile-onset hypophosphatasia(HPP), and Kanuma, an enzyme replacement for patients with lysosomal acid lipase deficiency (LAL-D).
The company also has other compounds in its pipeline, including WTX101 for Wilson Disease and SYNT001 in early clinical development for Warm Autoimmune Hemolytic Anemia (WAIHA), Memphigus Vulgaris (PV) or Pemphigus Foliaceus (PF). It also has several preclinical compounds.
Orloff says, “We’re a rare disease company moving from ultra-rare to rare, trying to diversify beyond complement. But clearly, we have expertise in complement-based therapeutics. We’re open to new indications that includes neurology, which is a growing business and central to future growth, but we also plan to develop targeted therapeutics outside the complement space. We’ve been active on the business development front to shore up the pipeline, such as a partnership with amyloidosis, an acquisition for Wilson’s disease, and others. The pipeline has really been vastly improved and bolstered by our development efforts in the last year.”
