Sanofi and Wave Life Sciences are using their time at the annual meeting of the American Thoracic Society in Orlando to share updated data for their next-gen attempts to treat a protein deficiency disorder that hasn’t seen significant innovation in about four decades.
French pharma Sanofi today shared detailed data behind its phase 2 win last fall, where efdoralprin alfa—acquired in the $1.7 billion buyout of Inhibrx—topped CSL’s standard-of-care Zemaira at boosting levels of alpha-1 antitrypsin. Those with alpha-1 antitrypsin deficiency (AATD) lack this critical protective protein that shields the lungs from inflammatory damage, putting them at risk of emphysema.
An infusion of efdoralprin alfa every three weeks increased average AAT levels in the blood to 24.1 micromolar (μM), Sanofi announced today, as measured just before the patient’s next infusion. That compares to 16.8 μM if given every four weeks, and 7.6 μM for once-weekly Zemaira.
The trial, codenamed ElevAATe, enrolled 99 patients across its three arms and assessed outcomes after 32 weeks.
“Across the board, we had very strong, statistically significant results,” Alaa Hamed, M.D., Sanofi’s global medical head of rare diseases, told Fierce Biotech. “We were able to establish a level of functional AAT that's within the normal range.”
Sanofi is now discussing potential next steps with the FDA, Hamed added.
Both Zemaira and efdoralprin alfa are versions of AAT, but while Zemaira is sourced directly from donor blood, efdoralprin alfa is a recombinant protein engineered to last longer in the body. Protein replacement with medicines like Zemaira is currently the only available option for AATD patients.
The levels of AAT achieved by Sanofi’s molecule far outstrip the 11 μM cutoff generally considered to be the minimum requirement for lung protection.
“Since AAT level is a major predictor of clinical phenotype and progression in untreated patients, sustaining levels as close to normal as possible has long been a goal of treatment, and this study goes some way toward that,” Alice Turner, Ph.D., a respiratory physician at the University of Birmingham in the U.K., told Fierce.
Turner did not have patients in the ElevAATe trial but has consulted for Sanofi on AATD and related fields.
Patients with AATD are susceptible to symptom flares commonly called exacerbations, which can be caused by infections or environmental triggers like air pollution. These bouts of worsened coughing and shortness of breath can progressively damage the lungs over time.
Sanofi studied these exacerbations as a safety endpoint and saw numerically lower rates of them in patients given efdoralprin alfa compared to Zemaira; 34.1% and 42.1% of patients had one in the three-week and four-week arms, respectively, compared to 44.4% for weekly Zemaira.
“There is a level of protection here that manifests itself in protection from these infections and other issues,” Hamed said.
Efdoralprin alfa’s ability to improve clinical outcomes is a focus of ElevAATe’s ongoing open-label extension, and is something Turner has her eyes on.
“Further data on the clinical effectiveness outcomes will be vital,” she said. “Results from the open-label study should give this in due course.”
Wave Life Sciences is taking a radically different approach than Sanofi to treat AATD. Instead of enzyme infusions every few weeks, Wave envisions a monthly shot that patients can give themselves to turn their bodies into healthy AAT factories.
“For protein replacement, it's kind of like a bucket with holes in the bottom,” Wave CEO Paul Bolno, M.D., told Fierce. An infusion refills the bucket, but when exacerbations occur, the pool of AAT is drained, leaving patients vulnerable to further flare-ups until their next treatment.
Wave’s candidate, WVE-006, is an RNA editor meant to tweak one toxic form of AAT into the healthy variant, so that patients are protected no matter how many exacerbations they may face in between doses.
Wave today shared that a 400-mg monthly dose of WVE-006 produced 13.6 μM of total AAT, with 7.98 μM of healthy protein, in the phase 1/2a RestorAATion-2 trial. More important for Bolno, though, is the reduction of the mutant Z variant of AAT, which can build up in the liver and cause liver disease. Wave’s studies focus on the subset of AATD patients who have two copies of the Z variant.
“That's what builds up and causes liver dysfunction, and we see over 70% decrease in Z protein,” Bolno explained. Protein replacement, he added, does nothing to reduce Z protein levels.
Beam Therapeutics is also focused on the Z variant, but it's pursuing a one-time tweak to patients’ DNA using in vivo gene editing. Beam’s phase 1/2 trial cleared a safety hurdle last year and “set the bar for efficacy in the space,” an analyst said at the time.
While a one-time gene edit may on paper seem superior to monthly doses of an RNA editor, Bolno doesn’t see it that way. He thinks getting enough DNA editing to have a therapeutic effect with just one dose will be tricky, and repeat dosing comes with safety concerns. Plus, a more short-lived medicine based on RNA has the benefit of being reversible.
“Reversible is a feature, not a bug, so long as you can push the durability out,” Bolno said of Wave’s approach.
Wave’s partner GSK recently declined to take over development of WVE-006, so Wave is now in discussions with the FDA about potential accelerated approval for the candidate. These discussions, Bolno said, have not been derailed by the recent leadership exodus at the regulator. The biotech hopes to have feedback from the agency by the middle of the year.
Though Wave is only pursuing a subset of AATD, Bolno believes RNA editing can make the need for protein replacement obsolete for patients with two copies of the Z gene variant.
“We're starting and very much staying focused now on demonstrating this in the ZZ population,” the CEO told Fierce.
The reverse is true for Sanofi, where the focus is currently not on reducing Z protein or protecting the liver but could be down the line, Sanofi’s Hamed said. He hopes efdoralprin alfa is the beginning of a burgeoning AATD portfolio for the French drugmaker.
While it may be tempting to compare Sanofi, Wave and Beam’s data, Birmingham’s Turner cautions against it.
“I think it’s too early to comment on relative approaches until we get something more solid,” she told Fierce.
Even though Sanofi and Wave are taking different tacks to address a disease long starved of new medicines, Hamed and Bolno both agree that AATD diagnosis remains a key challenge for the field.
“Alpha-1 antitrypsin deficiency is massively underdiagnosed at the moment,” Hamed said. “We believe that 90% of the patient population is undiagnosed.” This is because even though guidelines for chronic obstructive pulmonary disease (COPD) recommend testing patients for AATD, the condition is so rare that many patients don’t get screened for the condition.
“They are treated as normal COPD patients, but in reality, the genetic causes of this condition is what needs to be treated,” Hamed said.
Diagnostic rates are picking up as more clinical trials are done, Bolno added, and the Alpha-1 Foundation has a large effort underway to increase awareness of the disease. Many patients are misdiagnosed as having asthma as children, he said.
“It's not until they're a little bit older where somebody will be like, ‘this is not asthma,’” Bolno said.
https://www.fiercebiotech.com/biotech/sanofi-and-wave-post-genetic-disease-updates-race-end-fields-40-year-drought
