Sickle Cell Innovators Required: Emmaus' Pending Approval Highlights Rare Disease Void
Executive Summary
FDA approval is likely for Emmaus' sickle cell drug L-glutamine this summer, representing the first new product for the disease since 1998 – a decision FDA advisory committee panelists hope will spur more innovation.
As potentially the first new drug to approach the sickle cell disease market in nearly 20 years and with a limited late-stage pipeline, reception this summer for Emmaus Life Sciences Inc.’s L-glutamine is likely to be strong despite the drug showing only modest benefit in a Phase III trial.
Despite quibbles over the efficacy analysis of the Phase III data, L-glutamine looks set for a US approval following a 10-3 vote in favor of the drug's benefit/risk profile from the FDA's Oncologic Drugs Advisory Committee (ODAC) on May 24. The panelists also hope that one new approval will convince drug development companies to pour more resources into sickle cell R&D.
If approved, L-glutamine will be the first new drug for sickle cell since 1998 and only the second approved drug in the US for treatment of the disease – which, though a rare condition, affects around 100,000 Americans. Bristol-Myers Squibb Co.'s Hydrea (hydroxyurea) is currently the only approved treatment to reduce the frequency of sickle cell crises.
ODAC panelists had several questions for Emmaus about the clinical studies presented in L-glutamine's new drug application (NDA), particularly on the high number of patient dropouts seen in both Phase II and Phase III studies of L-glutamine. However, the panel eventually voted in favor of the drug because of the lack of alternative therapies available on the market and the low toxicity seen with L-glutamine use.
Brian Rini, professor at the Lerner College of Medicine and chair of the committee, who voted in favor of Emmaus' drug, highlighted that even modest benefit will have a vital effect for patients with sickle cell disease. He said the drug had shown a "modest but consistent benefit" and would have a positive clinical impact for patients.
Rini added that he hopes approval of a new sickle cell therapy will spur more research into the disease.
Harvard Medical School Professor Harold Burstein, who also voted yes, concurred, noting that he hoped an FDA approval for L-glutamine will "set the stage for more innovation in sickle cell anemia." He added that even one fewer hospital visit a year, the average reduction seen in Phase II and III trials of L-glutamine, is a clear meaningful benefit for sickle cell patients.
Meanwhile, Mayo Clinic hematologist Michael Menefee voted against approval of the drug, stating that while it appears to have a "clear signal of activity," a better clinical study can be done. He had qualms over the long-term use of the drug: sickle cell is a chronic condition and L-glutamine, while alleviating the disease, is not a cure. Emmaus told the committee it does not have any data for long-term use of the drug past the 48-week timeframe of its Phase III study.
Clinical Trial Issues
Several panelists commended Emmaus for its commitment to sickle cell research and accepted the issues that can occur in carrying out a registrational study in chronically ill patients. They noted that the added burden of a clinical trial is possibly more than can be expected of some patients.
Emmaus' data for L-glutamine were disrupted by very high dropout rates in both the placebo and active drug arms of its Phase III trial. Reasons for patients not completing the study were poorly documented and this issue plagued the ODAC's Q&A session with the company.
However, Heidi Klepin, associate professor of internal medicine, hematology and oncology at Wake Forest University, said the issue of dropouts in Emmaus' studies was not a "fatal flaw" for the drug and said efficacy was still shown. Other panelists agreed that clinical studies in sickle cell patients are complex and non-completion occurrences should be expected.
Overall most committee members were satisfied that L-glutamine's benefits outweigh its risks as the drug presented no toxicity red flags in the clinic. But Grzegorz Nowakowski, another Mayo Clinic physician, raised concerns that approving a product with questionable efficacy could deflate the industry's R&D focus on, and momentum for, improving treatment options in sickle cell.
L-glutamine is already approved in the US, where it is known as Endari, for the treatment of short bowel syndrome.
Limited Sickle Cell Pipeline
There are a handful of drugs in Phase III trials for sickle cell disease, according to data from Biomedtracker, though none of these compounds are expected to reach the market soon. One of the most promising compounds in development is Global Blood Therapeutics Inc.'s GBT440, an orally-available allosteric modifier of hemoglobin structure, but Phase III completion for this product is not anticipated for another couple of years.
GBT440, which works by increasing the affinity of hemoglobin for oxygen, is highlighted by Biomedtracker analysts as a "potentially disease-modifying therapy" for sickle cell disease. However, one major question for the drug that could affect larger clinical studies is whether it could impair delivery of oxygen to tissues as a side effect.
Data for GBT440 from the pivotal Phase III HOPE study, which will provide more insight into the safety profile of Global Blood's therapy, are expected in the first half of 2019.
There are three other sickle cell drugs listed as being in Phase III development, but these target the symptoms of sickle cell rather than the cause. However, there is still an unmet need for new therapies targeting the wide-ranging symptoms of the condition.
Major complications of sickle cell include: pain crises, chronic pain, severe anemia, infections, acute chest syndrome, eye problems, heart disease, stroke, kidney and liver complications, joint complications and delayed growth and puberty in juveniles.
Phase III Sickle Cell Therapies
Drug Name | Lead Company | Lead Indication | Likelihood of Approval | Drug Classification | Route of Administration |
GBT440 | Global Blood Therapeutics | Y | 62% (2% Above Avg.) | New Molecular Entity (NME) | Oral |
Pedroxa | EDE Pharmaceuticals, Inc. | N | 60% | Non-NME | Oral |
Rivipansel | Y | 60% | NME | I.V. | |
SC411 | Y | 60% | Non-NME | Oral |
Meanwhile, according to Biomedtracker, there are also nine compounds in Phase I or I/II trials, including four biologics and two NMEs, and five Phase II compounds in development, including three biologics and two NMEs.
Novartis AG is one big pharma that has made a move into sickle cell research more recently, having acquired Selexys Pharmaceuticals Corp. in November 2016 for its Phase II candidate SEG101 (crizanlizumab) in a deal worth up to $665m. (Also see "Sickle Cell Data Show Value Of Novartis’s Recently Acquired SEG101" - Scrip, 5 Dec, 2016.)
Novartis expects to submit SEG101, a humanized monoclonal antibody directed against P-selectin, for regulatory approval for sickle cell pain crises in the US in early 2018.
Other treatment options – focused on curative approaches for sickle cell rather than disease management – are also being explored earlier in the pipeline, such as cell and gene therapies.
Bluebird bio Inc. has the most advanced gene therapy for sickle cell in clinical development and a case study for the treatment, LentiGlobin, was published in the New England Journal of Medicine in March. The data showed that 15 months after treatment, the level of therapeutic ant-sickling β-globin remained high (approximately 50% of β-like–globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease.