Adakveo ‘Important’ and Safe New Treatment for VOC Crises in Sickle Cell, SUSTAIN Researcher Says

Adakveo ‘Important’ and Safe New Treatment for VOC Crises in Sickle Cell, SUSTAIN Researcher Says

Adakveo (crizanlizumab) is an “important addition” to the care of sickle cell disease, a safe and effective therapy that works against painful vaso-occlusive crises (VOCs) in SCD patients and is likely do so over the long term, said the doctor who led the clinical trial that supported its U.S. approval.

“We’re very excited that we have this new drug … an additional therapy to decrease sequential painful crisis in people with sickle cell disease,” Kenneth Ataga, MD, director of the Center for Sickle Cell Disease at the University of Tennessee Health Science Center (UTHSC) and principal investigator of the Phase 2 SUSTAIN trial, said in an interview with Sickle Cell Disease News. Ataga earned his medical degree at the University of Benin in Nigeria and specializes in red blood cells disorders like sickle cell.

Novartis, which developed and markets Adakveo, expects it to be available “in coming days.”

Kenneth Ataga
Dr. Kenneth Ataga. (Photo courtesy of UTHSC)

VOCs are caused by the clotting of blood vessels, a complication more likely in people with SCD than others because of a mutation in the gene that produces the hemoglobin protein. Their red blood cells are sticky, and have an unusual sickle-like shape that makes them more prone to forming large clumps that block small blood vessels.

Adakveo was approved by U.S. Food and Drug Administration (FDA) for patients ages 16 and older on Nov. 15, the first SCD medication that seeks to reduce the frequency of VOCs by blocking the activity of P-selectin, an adhesion protein normally found on the surface of endothelial cells (which line blood vessels) and platelets.

P-selectin promotes the sticking of sickle-shaped red blood cells to each other and to vessel walls in sickle cell patients, obstructing their small vessels and increasing the risk of VOCs.

“Going into a trial with a drug that has a plausible mechanism of action that looks like it would work — you always hope and expect that it would work,” Ataga said. “But I’ve been in this field for a bit, and I’ve seen drugs that seemed they would work and have not.”

That wasn’t the case for Adakveo, he added, “and that was good to see.”

Ataga was particularly pleased with the good safety seen in treated patients in the SUSTAIN study, and the significant efficacy shown at its higher, 5 mg/kg dose — without new safety concerns.

Adakveo is not the only FDA-approved medicine that helps to lessen VOC episodes in SCD, Ataga noted. Hydroxyurea, first approved in 1998 to treat adults with SCD, and Endari (L-glutamine), approved for those with age 5 and older in July 2017, have both “been shown to decrease episodes of painful crises,” he said.

Hydroxyurea works by boosting the production of hemoglobin F (also known as fetal hemoglobin), which carries oxygen in a developing baby but is largely lost in infancy. Compared to the adult form of hemoglobin, hemoglobin F is more effective at transporting oxygen.

By increasing hemoglobin F levels, hydroxyurea improves oxygen transport in SCD patients and lessens their chances of anemia, a condition marked by blood that cannot carry enough oxygen.

Endari, by Emmaus Life Sciences, works in a different way. It increases the amount of free glutamine, an amino acid that plays an important role in cell metabolism, which is taken up by sickle red blood cells to produce anti-oxidant molecules. These molecule help the cells neutralize the damaging effects of oxidative stress and regain an oxygen-supporting flexibility.

“Although both drugs [hydroxyurea and Endari] can decrease the number of vaso-occlusive crises … patients taking these medicines can still get sick, they can still have painful crisis and other complications,” Ataga said. “It’s clear we need other medicines.”

And it’s clear Adakveo “is an important addition to these treatments,” he said, because it brings a new mechanism of action into play.

“I think what most of us envisage” as physicians, he added, “is having patients with sickle cell disease who get different drugs that work in different ways to improve their care.”

A safe and effective prophylactic, possibly over  long term

Data from SUSTAIN (NCT01895361) showed that in patients treated at the high 5 mg/kg dose, Adakveo significantly reduced the frequency of annual VOCs by a mean of 45.3% compared to those given placebo. In these two trial arms, 62.9% had two to four VOC crises in the year before the study’s start, and 37.1% between five and 10.

Importantly, reductions were seen — including in those treated at the low 2.5 mg/kg dose — regardless of patients’ specific mutations or whether they were also using hydroxyurea at the time, as two-thirds of trial participants were, Ataga said.

This co-use left him hopeful that Adakveo won’t interfere with other medications patients might be taking, because in SUSTAIN no “adverse interactions” were found.

People enrolled in SUSTAIN were given Adakveo for about one year. But as it’s meant to be a prophylactic, or preventive, VOC treatment, patients needing Adakveo might use it for years.

Is its efficacy and safety likely to hold over years of use?

“The results [from SUSTAIN] were very important, and very impressive,” Ataga said, adding that he thought it likely to benefit both patients whose pain crises are severe enough to require hospitalization and those who can manage a given crisis on their own.

“My hope, obviously, is that it continues to be efficacious in patients with sickle cell disease,” he said. “But we’ll have to see how things work out” once Adakveo’s in long-term, clinical use.

As a treating physician, Ataga also had no problem with its administration by intravenous (IV) infusion and possibly preferred it to an oral pill.

“My experience from doing this trial suggests that some patients actually seem to like the idea of taking this drug, for one,” he said.

Orals are great for convenience, but unlike an infusion done at a clinic, patient adherence can be guesswork. “When patients get treatments like this, unlike pills at home, the doctor is able to access who’s taking the medicine. If a patient misses an appointment, we can follow up with them.

“I’m optimistic that it [IV infusion] will not be much of a problem.”

Monthly dosing, and pricing

Adakveo’s recommended dosing is 5 mg/kg by a 30-minute IV infusion once each month, after two initial doses given two weeks apart. The number of vials needed depends on patients’ weight, but Novartis — in announcing the drug’s list price — indicated that teenagers and adults will use three to four vials, each with 100 mg/10 mL of crizanlizumab, per monthly treatment.

That could add up for patients, as Adakveo is entering the U.S. market with list price is $2,357 per vial, or $7,071 to $9,428 a month. 

Novartis, in an email response to questions, said it has “taken a thoughtful approach to the price of Adakveo — balancing the innovation it brings to the treatment of sickle cell disease, the benefits it can provide to patients, and the importance of ensuring that appropriate patients have access to it.”

Ataga largely agreed, speaking of a need to recognize costly years of work.

“On face value, the number looks like it’s a lot. But I know that investment has to be rewarded, because a lot of work has gone into making this drug available to our patients,” he said. “But at the same time, the drug has to be affordable and has to be available to patients.”

Patients don’t really pay list prices, but even with insurance are expected to pick up co-pays. For Ataga, the cost and range of these co-pays are a main concern, as is “what other avenues or resources are in place” for people without insurance who need access to Adakveo.

“That’s what’s important to me as the provider,” he said.

Still to come

Adakveo-treated patients clearly showed a “dose-dependent response” in SUSTAIN, with a lowering of VOC events in both low- and high-dose group, although at a rate only significant in the 5 mg/kg arm. Safety was similar in both groups.

But crizanlizumab’s potential is far from being fully established. Among clinical trials now underway in this treatment — under Novartis’ SENTRY trial program — are:

  • A double-blind and placebo-controlled Phase 3 study, STAND (NCT03814746), that is testing crizanlizumab at its approved dose and a higher dose of 7.5 mg/kg. This trial is in up to 240 SCD patients, ages 12 and older, with at least two VOCs in the previous year, and is now enrolling at sites across the U.S., Europe, and in Brazil and Lebanon.
  • An open-label Phase 2 study, called SOLACE-kids  (NCT03474965), in up to 100 infants and children between 6 months and 17 years old with at least one VOC in the prior year, that might help expand crizanlizumab to pediatric SCD patients. This dose establishing trial, largely looking at crizanlizumab’s pharmacologic properties (how the drug affects the body and how the body affects the drug) and safety, is currently recruiting at 41 sites across the U.S., Canada, Europe, and elsewhere.
  • SOLACE-adults (NCT03264989), also Phase 2, is doing the same in up to 55 patients, 16 to 70 years old, with prior VOC crises. After safety is established in the first 45 at Adakveo’s approved dose, 10 more patients will be enrolled and treated with the potential 7.5 mg/kg higher dose. Recruitment is underway at sites across the U.S.
  • A single-arm Phase 2 study, SPARTAN (NCT03938454), is evaluating the efficacy and safety of Adakveo, at 5 mg/kg, in patients with priapism, a sustained and painful erection that affects men with sickle cell due to trapped blood. This trial is now enrolling up to 56 patients, age 16 and up, at two U.S. sites.
  • A Phase 2 trial called STEADFAST (NCT04053764) is looking at crizanlizumab’s effects, added to standard of care, on renal function in up to 170 patients, 16 and older, with chronic kidney disease related to SCD. It is now enrolling at its single site in Madrid.

STAND’s primary goal (endpoint) is to evaluate how well Adakveo reduces the frequency of annual VOCs requiring a medical facility visit. Its 15 secondary endpoints will also assess crizanlizumab’s pharmacokinetic profile (a drug’s movement in, through, and out of the body), as well as changes in hemoglobin, and VOC emergency room visits and hospitalizations,

Importantly, along with SOLACE-kids, a secondary STAND goal is measures of anti-drug antibodies produced that could render this treatment ineffective.

“Because it [Adakveo] is an antibody, there’s always that theoretical concern that patients might develop neutralizing antibodies over time,” Ataga said. “That wasn’t a concern during the SUSTAIN trial, and hopefully it won’t be a big concern going forward. … we’ll have to see things work out,” but “my expectation is that neutralizing antibodies will be tested.”

Between 900 and 1,000 adults with sickle cell are treated at UTSHC’s two clinical sites, Regional One Healthcare and Methodist University Health, each of which have an SCD-dedicated center. Adakveo will be among the treatment options offered these UTSHC patients.

“Yes, definitely,” Ataga said. “Even before it was approved … I was talking to my patients about the fact that this drug was likely coming out soon.

“As a provider who takes care of patients with sickle cell disease, I’m very excited about the fact that we have a new drug that has been shown to be efficacious at decreasing the sequence of painful crisis in people with sickle cell disease, and also has a good safety profile,” he added.

“We look forward to getting experience with this drug, and having this drug to help improve the lives of our patients.”

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
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Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
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Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.