Cell & Gene Therapy: Balancing Hope & Promise for Sickle Cell Therapies

Sickle Cell Disease

The genetic mutation that causes sickle cell disease was first discovered in 1956, but only recently have any drugs have been approved to treat the condition. None, however, show significant impacts on organ disease, and there are great unmet needs for prophylaxis as well as severe disease in acute care settings.

On October 12, biopharma companies came together to discuss this at the Cell & Gene Meeting on the Mesa, hosted by the Alliance for Regenerative Medicine. They recognized that developing a therapy is merely the beginning of what is needed to connect patients with sickle cell disease to next-level therapies.

“The great hope is for a cure,” said Debbie Drane, SVP, global commercial development & TA strategy at CSL Behring. But “cure” means different things to different people and the industry must be very careful not to overpromise, and not to oversimplify the disease.

“You may cure the genetic defect, but have you cured the disease?” Amy Simon, M.D., chief medical officer at Beam Therapeutics, asked. “Most patients would agree they were cured if they…were able to live a normal life.” Alternatively, a therapy that eliminates the noticeable disease events from a person’s life may be perceived by some patients as a cure, but undetectable events may occur that contribute to disease.

“If you start early and treat a young patient, sickle cell therapy can transform a life and the family’s life. That’s about as close to a cure as we get,” said Edmond Chen, M.D., VP and head of clinical development – hematology at Editas Medicine. “When you treat older patients, they will have sequelae (that must be treated), so ‘cure’ probably would not be a justified use of the word.”

Today, drug developers can address the root cause of sickle cell disease. “We can lower hemoglobin S to levels that are quite striking, and we’re seeing the elimination of the vaso-occlusive crises. These are huge changes we’ve been working towards for years,” Simon said.

“Most of our genetic cures actually are genetic workarounds,” said Sandy Macrae, Ph.D., president and CEO of Sangamo Therapeutics. “We replace one gene with a normal gene, but determining what constitutes ‘normal’ involves another discussion about such details as which single nucleotide polymorphisms (SNPs) should be included.”

Stem cell transplants currently are approved only for the most serious cases. Transplantation is an arduous process that takes up to a year of planning and preparation. Beam Therapeutics and others want to streamline the process by delivering gene editing tools directly to the hemopoietic stem cells. That approach could eliminate the need for transplant centers and dramatically lower treatment costs, “though it’s still expensive,” Simon said. Nonetheless, “it’s a step in the right direction.”

Reimbursement is a universal hurdle. One option, advocated by bluebird bio, involves reimbursement over time. As bluebird Chief Commercial Officer Thomas Klima, explained, “our goal is to achieve access to medications for patients, but payers and governments aren’t set up to support payment over time, especially in a resource-constrained environment.”

Therefore, bluebird bio began working early with payers to develop innovations and practical solutions. “There’s a tradeoff between short-term (sticker) shock and the long-term potential benefit…and patients in the U.S. change healthcare plans a lot,” he admitted.

As Drane added, “we have to educate payers and public officials about the value – not just the cost – of cell and gene therapy. These therapies bring great value to patients, caregivers and society in general, but until we have proof of durability, that’s a difficult discussion to have.”

Companies’ responsibilities extend beyond developing therapies to addressing, to some extent, health disparities that affect their patients’ ability to access treatment.

Sickle cell disease affects approximately 100,000 people in the United States, and 90% of them are African American. As companies, “we need to talk with the patient community,” Macrae said. “We need to be very fair and very clear to avoid engendering unjustified hope.” That entails explaining the data very clearly, in ways the sickle cell community can understand, and working with patient advocacy organizations so they can explain to their constituencies the treatment options, their risks, and what they realistically can expect.

“Be fair and balanced when you talk about what you can do, and get their advice. What we think is a cool endpoint may not be theirs,” Macrae added. Those discussions require putting the therapy and the disease in perspective. For example, an innovative treatment doesn’t obviate the risk of contracting other conditions later on. Nor may it necessarily cause them. Either way, treatment developers will want to know conditions that emerge so they can determine how it affects the therapy and, possibly, vice versa.

The need for continued, long-term follow-up also must be pointed out to patients receiving gene therapy. “Once you alter DNA, you have a responsibility to follow-up, and you have to plan for this for your future company,” Macrae said. For context, he noted that some HIV studies have been running for 15 years.

The panelists all advised working closely with the patient advocate community. Patients want predictability, they said.

Beyond educating patients and patient advocates, Klima stressed, biopharma companies also need to find solutions to select healthcare disparities. For bluebird bio, that means removing non-clinical barriers whenever possible. In sickle cell therapy, that sometimes means helping distant patients access treatment sites or find lodging for the duration of the therapy. As an industry, he said, “we need to ensure we have these things in place.”

“There’s also a difference in what you can do for patients during clinical trials and what you can do once the therapy is approved,” Chen pointed out. “For cystic fibrosis, some of the foundations have tremendous support. Hopefully, the sickle cell community will come together similarly.”

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