January 21, 2020—(BRONX, NY)—A clinical trial has found the drug luspatercept significantly reduced the need for blood transfusions in people with lower-risk myelodysplastic syndromes (MDS), a group of bone marrow disorders that leave people with many defective blood cells and too few normal ones. Approval by the Food and Drug Administration (FDA) would make luspatercept the first new drug available to MDS patients in 12 years. Results of the phase 3 clinical trial were published online January 9 in the New England Journal of Medicine (NEJM).

Amit K. Verma, M.B.B.S.Faculty ProfileResearch Profile

“A large proportion of patients with lower-risk MDS eventually become anemic and require periodic blood transfusions,” said study co-author Amit Verma, M.B.B.S., professor of medicine and of developmental and molecular biology at Albert Einstein College of Medicine and director of the division of hemato-oncology at Montefiore Health System. “The transfusions are lifesaving but are also costly and inconvenient and can lead to serious complications. This drug would greatly improve the quality of life for these patients.” Dr. Verma is also a member of the National Cancer Institute-designated Albert Einstein Cancer Center and a co-leader of its stem cells, differentiation and cancer research program.

Restoring Red Blood Cells to Alleviate Anemia

Nearly a decade ago, Dr. Verma, in collaboration with Ulrich Steidl, M.D., Ph.D., was among the first researchers to show that MDS arises from defective hematopoietic (blood-forming) stem cells in the bone marrow. The identification of pathways that are targeted by luspatercept is based on Dr. Verma’s more recent MDS research.

In studies using MDS patient samples and mouse models of MDS, Dr. Verma found that the SMAD2/3 signaling pathway, which ordinarily inhibits red cell production by stem cells, was overactive in MDS and contributed to anemia. He then showed that blocking this pathway can restore red cells to a mature, functional state and alleviate anemia. Today, the online edition of the Journal of Clinical Investigation published a review of the biological basis for developing luspatercept; co-authors included Dr. Verma and scientists at Acceleron Pharma responsible for develoing the drug.

Luspatercept (Reblozyl) is a recombinant fusion protein, created by joining two or more genes that originally coded for separate proteins. The fusion protein binds with select TGF-β (transforming growth factor-β) family molecules. This binding prevents the TGF-β family molecules from contacting receptors on the surface of blood-forming stem cells to turn on SMAD2/3 signaling. The result: SMAD2/3 signaling is inhibited, enabling red cells to reach maturity.

Fewer Blood Transfusions Needed

In the clinical trial described in the NEJM, 229 patients with lower-risk MDS (who did not respond to anemia drugs and required transfusions every month or two) were randomly assigned to receive luspatercept (via injection) or placebo every three weeks for at least six months. Patients were recruited from Montefiore and other centers around the United States.

Thirty-eight percent of the patients treated with luspatercept were able to go eight weeks or longer without a transfusion, and approximately four out of 10 of those responders remained transfusion-free for one year. By contrast, only 13 percent of patients in the placebo group were able to go without transfusions for eight or more weeks.

The FDA approved luspatercept in November 2019 for the treatment of anemia in adult patients with beta thalassemia who require regular red cell transfusions. The agency is scheduled to consider approving luspatercept for MDS this April.

About MDS

MDS, a cancer of the bone marrow, occurs when blood-forming cells called “blasts” develop abnormally and multiply rapidly. Abnormal blasts churn out many abnormal blood cells and relatively few normal ones. Different types of MDS can decrease different blood cells—most commonly red cells, resulting in anemia. The incidence of MDS in the United States is unclear, with estimates ranging from 10,000 to 40,000 new cases annually.

Patients with MDS are typically treated with specialized chemotherapies to reduce the number of blasts, plus symptom management and supportive care including blood transfusions. Treatment puts some patients into remission, sometimes for years, but the disease almost always returns. Survival varies widely depending on the disease type; it ranges from nine months for those with very high-risk MDS to nearly nine years for those with very low-risk disease.

The only cure is a bone-marrow transplant—a therapy not easily tolerated and therefore reserved for the youngest, most resilient patients. Most MDS patients, however, are elderly. Deaths result from bleeding, infection due to low blood-cell counts, and from MDS progressing to acute myeloid leukemia, which occurs in about one-third of MDS patients.

The NEJM article is titled, “Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes.” The other contributors are: Pierre Fenaux, M.D., Ph.D., Uwe Platzbecker, M.D., Ghulam J. Mufti, F.R.C.P., Guillermo Garcia-Manero, M.D., Rena Buckstein, M.D., Valeria Santini, M.D., María Díez-Campelo, M.D., Ph.D., Carlo Finelli, M.D., Mario Cazzola, M.D., Osman Ilhan, M.D., Mikkael A. Sekeres, M.D., José F. Falantes, M.D., Beatriz Arrizabalaga, M.D., Flavia Salvi, M.D., Valentina Giai, M.D., Ph.D., Paresh Vyas, B.Ch., B.M., David Bowen, M.D., Dominik Selleslag, M.D., Amy E. DeZern, M.D., Joseph G. Jurcic, M.D., Ulrich Germing, M.D., Katharina S. Götze, M.D., Bruno Quesnel, M.D., Ph.D., Odile Beyne-Rauzy, M.D., Thomas Cluzeau, M.D., Maria-Teresa Voso, M.D., Dominiek Mazure, M.D., Edo Vellenga, M.D., Ph.D., Peter L. Greenberg, M.D., Eva Hellström-Lindberg, M.D., Amer M. Zeidan, M.B., B.S., M.H.S., Lionel Adès, M.D., Amit Verma, M.D., Michael R. Savona, M.D., Abderrahmane Laadem, M.D., Aziz Benzohra, M.D., Jennie Zhang, M.S., Anita Rampersad, B.A., Diana R. Dunshee, Ph.D., Peter G. Linde, M.D., Matthew L. Sherman, M.D., Rami S. Komrokji, M.D., and Alan F. List, M.D.The authors’ full names and affiliations are listed in the online appendix.

The study was supported by grants from Celgene in collaboration with Acceleron Pharma. Dr. Verma reported receiving advisory board fees from Acceleron Pharma, grant support from Bristol-Myers Squibb, Celgene, and Eli Lilly, and receiving consulting fees from and holding stock options in Stelexis. Potential conflicts of interest for the other authors are listed in the online article.

The JCI paper is titled, “Biological basis for efficacy of activin receptor ligand traps in myelodysplastic syndromes.” The other Einstein contributors are Srinivas Aluri, Ph.D., Nishi Shah, M.D., and Tushar D. Bhagat, Ph.D. Additional authors are Rajasekhar N.V.S. Suragani, Ph.D., Mark J. Alexander, and Ravi Kumar, Ph.D., at Acceleron, Cambridge, MA; Rami Komrokji, M.D., at Moffitt Cancer Center, Tampa, FL.

RK, MA and RS are employees of Acceleron.