Keeping Track: A Busy Week For Regenerative Medicine, A Surprise Priority Review For Vascepa, And Tazemetostat Aims For Accelerated Approval
Executive Summary
The latest drug development news and highlights from our US FDA Performance Tracker.
The long Memorial Day weekend didn't slow down the US Food and Drug Administration and industry, which produced a burst of drug development news in the closing days of May. Here's your news in brief:
Regenerative medicine sponsors stole a chunk of the spotlight. Fibrocell Science Inc. reeled in a regenerative medicine advanced therapy (RMAT) designation for its recessive dystrophic epidermolysis bullosa (RDEB) gene therapy FCX-007, and Mesoblast Ltd. started a rolling biologics license application submission for its acute graft versus host disease (aGVHD) cell therapy remestemcel-L.
Amarin Corp. PLC might be adding a cardiovascular (CV) risk reduction indication to the label of its Rx-grade fish oil Vascepa (icosapent ethyl) sooner than expected after learning from the FDA that the supplemental new drug application will receive a priority review.
Epizyme Inc. is hoping to win the first FDA approval for epithelioid sarcoma in submitting its tazemetostat NDA to the agency for accelerated approval.
Meanwhile, Astellas Pharma Inc. updated the label of its myeloid leukemia (AML) drug Xospata (gilteritinib) to include overall survival (OS) data. However, with the approval of the sNDA comes a boxed warning for differentiation syndrome.
Additionally, the most recent breakthrough therapy designation (BTD) went to Bayer AG's Aliqopa (copanlisib) for a marginal zone lymphoma (MZL) indication.
Now, here's your news in less brief:
Regenerative Medicine Sponsors Sizzle As Summer Approaches
Despite what's been a quiet year so far for regenerative medicines, sponsors have started to make some noise in this arena in the waning days of spring.
Fibrocell is hoping to submit a BLA for its gene therapy FCX-007 in 2021 after scoring an RMAT for the treatment of RDEB.
In a 29 May announcement, Fibrocell explained that it expects to launch the Phase 3 clinical trial for FCX-007 during the second quarter of this year, with enrollment and dosing slated for completion by the third quarter of 2020. Enrollment in the open-label trial is expected to consist of 15-20 patients. The company added that data collection for the primary endpoint will be completed in the fourth quarter of 2020.
Fibrocell describes FCX-007 as "a genetically-modified autologous fibroblast that encodes the gene for COL7," the protein by which a deficiency causes RDEP, a rare, genetic skin disease with high mortality. The gene therapy also carries orphan drug, rare pediatric disease and fast track designations.
"By genetically modifying autologous fibroblasts ex vivo to produce COL7, culturing them and then treating wounds locally via injection, FCX-007 offers the potential to address the underlying cause of the disease by providing high levels of COL7 directly to the affected areas while avoiding systemic distribution," according to the biotech.
Continued development of the gene therapy will be facilitated by a recently announced a development and commercialization partnership with Castle Creek Pharmaceuticals LLC which brings Fibrocell $7.5m up front and a slew of near- and longer-term earnout possibilities. Castle Creek would get exclusive US commercial rights under the agreement. (Also see "Deal Watch: Gilead To Use Insitro’s AI/Functional Genomics Tech For NASH Targets" - Scrip, 17 Apr, 2019.)
So far, more than 20 gene therapies have made their way into the FDA's RMAT or BTD expedited development programs over the past several years. (Also see "Gene Therapies Make A Mark In US FDA Expedited Review Programs" - Pink Sheet, 26 Feb, 2019.)
But Fibrocell's RMAT marks only the second such designation publicly announced by a sponsor in 2019. The first of the year went to Canadian biotech ExCellThera's ECT-001 for the treatment of hematologic malignancies, which broke a five-month drought of no RMAT announcements. (Also see "Gene Therapies Make A Mark In US FDA Expedited Review Programs" - Pink Sheet, 26 Feb, 2019.)
Also making a splash during the week was Mesoblast, which announced on 29 May that it initiated a rolling BLA submission for its cell therapy remestemcel-L. Designed for the treatment of children with steroid-refractory aGVHD, the firm describes remestemcel-L as a treatment "comprising culture-expanded mesenchymal stromal cells derived from the bone marrow of an unrelated donor," that is administered through a series of IV infusions.
"Remestemcel-L has demonstrated immunomodulatory properties to counteract the inflammatory processes that are implicated in aGVHD by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues," the company explains.
In a 55-patient Phase III trial, remestemcel-L met the primary endpoint of increased day 28 overall response compared with a protocol-defined historical control rate of 45%. Mesoblast noted that the results are consistent with prior results from an expanded access program where remestemcel-L was used as salvage therapy in 241 children after failure of steroids and other agents.
Amarin Lands Unexpected Priority Review For Vascepa CV Risk Reduction
In a welcome regulatory surprise for Amarin, the FDA will give a priority review to the firm's cardiovascular risk reduction data for Vascepa, assigning a user fee goal date of 28 September.
The company is specifically seeking to update the prescription-grade fish oil's label with data from the REDUCE-IT CV outcomes trial, where Vascepa achieved a 25% relative risk reduction compared with placebo in the first occurrence of a major adverse cardiovascular event in patients with hypertriglyceridemia, including a 20% relative risk reduction in CV death. (Also see "Latest REDUCE-IT Results Bolster Case For Amarin's Vascepa Fish Oil Pill" - Scrip, 18 Mar, 2019.)
Upon submitting the sNDA, however, Amarin assumed it would be receiving a 10-month standard review clock. (Also see "Amarin's Vascepa Gets ADA Recommendation For Patients With Diabetes And High Triglycerides" - Scrip, 28 Mar, 2019.) Instead, a potential approval is now just four months away, the company reported 29 May.
The priority review is something of a breath of fresh air for the company, as Amarin's data was met with skepticism after patients receiving mineral oil as a placebo experienced an increase in LDL cholesterol, which potentially skewed Vascepa's CV impact. (Also see "Amarin's REDUCE-IT Data For Vascepa May Be Game-Changing, But Not Without Controversy" - Scrip, 12 Nov, 2018.) FDA evidently has a high initial opinion of the data by awarding the sNDA a priority review.
But an advisory committee could still be in the cards. Amarin has previously said it believes it is "likely" that an FDA panel will be convened to review he data, although the agency has not yet indicated whether it will do so, according to the company.
A purified formulation of the omega-3 fatty acid eicosapentaenoic acid, Vascepa is indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. However, labeling currently states that, "The effect of Vascepa on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined."
According to Amarin, an approval would make Vascepa the first drug "indicated to reduce residual cardiovascular risk in patients with statin-managed LDL-C cholesterol, but persistent elevated triglycerides, an important indicator of cardiovascular disease."
Epizyme Banks On ORR For Tazemetostat Accelerated Approval
Epizyme is taking the accelerated approval route in an effort to make its novel product candidate tazemetostat the first FDA-backed drug for epithelioid sarcoma, and the company is betting on a 15% objective response rate (ORR) to do so.
An FDA approval would give tazemetostat, a first-in-class EZH2 inhibitor, an indication for the treatment of patients with metastatic or locally advanced epithelioid sarcoma not eligible for curative surgery, Epizyme said 30 May.
Supporting the NDA submission is data from 62 patients enrolled in the epithelioid sarcoma cohort of an open-label, single-arm Phase 2 trial, where nine subjects (15%) demonstrated a confirmed partial response. Additionally, tazemetostat achieved disease control in 26% of epithelioid sarcoma patients who entered the study, according to data that will be presented at the American Society of Clinical Oncology 2019 annual meeting. Epizyme describes the trial as "the largest prospective clinical trial in epithelioid sarcoma with any approved or investigational anticancer treatment to date."
Nevertheless, it has been a rocky road for tazemetostat to the FDA so far. The drug was the subject of a partial clinical hold last year following a safety report of a pediatric patient developing a secondary T-cell lymphoblastic lymphoma, although the hold has since been lifted. (Also see "Tazemetostat Setbacks Hit Epizyme " - Scrip, 3 Aug, 2018.)
Conversely, curtting in tazemetostat’s favor is that it is a targeted therapy. The 62 patients from the Phase II trial all had INI1-negative epithelioid sarcoma, and the FDA could be swayed by the unmet need. Biomedtracker lists the likelihood of approval at 79%.
Epizyme noted it will be conducting a randomized, controlled trial of tazemetostat to support full approval for epithelioid sarcoma, which the biotech expects to initiate in the second half of this year. The company additionally plans to submit a tazemetostat application to the FDA for a follicular lymphoma indication in the fourth quarter of 2019.
Xospata Label's OS Data Addition Comes With Boxed Warning
Although Astellas successfully added OS data to the label of its AML drug Xospata, the label of the FLT3 inhibitor also now includes a boxed warning for differentiation syndrome.
Astellas announced 30 May that the Xospata's label has been updated following a review under the Real-Time Oncology Review (RTOR) pilot to feature final analysis data from the ADMIRAL trial, where Xospata recipients achieved a median OS of 9.3 months compared versus 5.6 months for salvage chemotherapy recipients.
The initial 2018 approval was based on the endpoints of complete remission (CR)/complete remission with partial hematologic recovery (CRh), the duration of CR/CRh and the rate of conversion from transfusion dependence to transfusion independence. (Also see "Keeping Track: US FDA Enters Year's Final Stretch With Tsunami Of Novel Approvals " - Pink Sheet, 1 Dec, 2018.)
But the label now contains a boxed warning stating that, " Patients treated with Xospata have experienced symptoms of differentiation syndrome, which can be fatal if not treated. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution." The initial 2018 label says that differentiation syndrome only occurred in 1% of patients, although the updated 2019 label notes it occurred in 3% of patients, and that nine of the 11 patients recovered after treatment or dose interruption.
CHRONOS-1 Nets Another Win For Aliqopa In Form Of BTD
Bayer AG's Phase II CHRONOS-1 study first helped the company's phosphatidylinositol-3-kinase (PI3K) inhibitor Aliqopa (copanlisib) nab an accelerated approval for the third-line or greater treatment with of adults with relapsed follicular lymphoma. Now, it helped the drug score a BTD for the third-line or greater treatment of adults with relapsed MZL, the company reported 29 May.
In the trial, Aliqopa demonstrated an overall response rate of 59.2% in the broader indolent non-Hodgkin's lymphoma (iNHL) population of 142 patients who received at least two prior therapies, as well as a 69.6% overall response rate in 23 patients specifically with relapsed or refractory MZL. The MZL subgroup also demonstrated a 78.3% overall response rate in an 18-month follow-up analysis.
An approval for MZL would expand Aliqopa's reach even further in the iNHL population, as the follicular lymphoma indication already covers the most common iNHL histological subtype. (Also see "Keeping Track: Biosimilar Submissions Galore (And An Approval), Bayer Gets An Oncology Approval, KemPharm Resubmits Apadaz NDA" - Pink Sheet, 17 Sep, 2017.) MZL also accounts for roughly 10% of the overall non-Hodgkin's lymphoma population in the US, according to Bayer.
Bayer has two ongoing Phase III studies testing Aliqopa in iNHL: CHRONOS-3 and CHRONOS-4. The placebo-controlled CHRONOS-3 trial is evaluating Aliqopa in combination with Genentech Inc.'s Rituxan (rituximab) on the endpoint of progression-free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment. CHRONOS-4, for its part, is comparing Aliqopa plus standard immunochemotherapy with placebo plus standard immunochemotherapy in patients with relapsed iNHL who have received between one and three lines of treatment. Primary endpoints include the occurrence of dose-limiting toxicities/adverse events and PFS, according to clinicaltrials.gov.
Revlimid Gets New Indication For Non-Hodgkin's Lymphoma
Speaking of non-Hodgkin's lymphoma, Celgene Corp.'s blockbuster multiple myeloma drug Revlimid (lenalidomide) was approved by the FDA 28 May in combination with Rituxan for treatment of adult patients with previously treated follicular lymphoma or marginal zone lymphoma.
The approval of Celgene's sNDA comes a month ahead of the 27 June user fee goal date. FDA had granted the combination treatment priority review.
This is the first FDA-approved combination treatment regimen for these indolent forms of non-Hodgkin's lymphoma that does not include chemotherapy.
The approval was based primarily on results of the randomized, double-blind, Phase III AUGMENT study, which evaluated Revlimid/rituximab versus rituximab plus placebo in patients with previously treated follicular lymphoma and marginal zone lymphoma. Patients treated with Revlimid/rituximab had a statistically significant improvement in the primary endpoint of PFS versus rituximab/placebo (39.4 months versus 14.1 months).
"Chemotherapy continues to be a standard of care for indolent forms of NHL, but most patients will relapse or become refractory to their current treatment," Lymphoma Research Foundation CEO Meghan Gutierrez said in a Celgene release. "This approval represents a new therapeutic option for previously treated patients with follicular and marginal zone lymphomas, including those who relapse or no longer respond to treatment."
The top-selling myeloma drug globally, Revlimid will face generic competition in 2022. It has been adding new indications as part of combinations. (Also see "Myeloma Milestones: Selinexor May Be Next Novel Agent While Established Drugs Expand Indications" - Scrip, 8 May, 2019.)
Rockwell Looks To Expand Triferic Franchise With IV Option
Rockwell Medical Inc. announced an NDA submission for a new IV formulation of Triferic (ferric pyrophosphate citrate) on 29 May, as it looks to build on its recent launch of the iron replacement product for delivery via hemodialysate. Triferic is used to maintain hemoglobin in patients with hemodialysis-dependent chronic kidney disease (HDD-CKD); the approved formulation is packaged in powder packets that are mixed with bicarbonate concentrate, which is then incorporated in the dialysate.
The IV Triferic clinical program used the FDA’s special protocol assessment (SPA) process, “through which the FDA agreed that an equivalence approach to Triferic delivered via hemodialysate (dialysate Triferic) would be acceptable for review,” Rockwell said. The NDA includes on an equivalence study showing that IV Triferic “delivers the same quantity of iron to patients as Triferic delivered via hemodialysate” and an open-label randomized multiple-period single-dose study to establish equivalence of doses between dialysate and IV administration.
Rockwell highlighted IV Triferic’s potential overseas. “We also see a substantial global market for IV Triferic, as many dialysis providers in large international markets predominantly use bicarbonate bags or cartridges comprising dry powder, and IV Triferic would integrate well with their existing protocols,” the company said.
Nektar Prepares For August Action On NKTR-181
FDA has extended the user fee goal date for Nektar Therapeutics’ novel mu-opioid NKTR-181 from 29 May to 29 August. Nektar’s Securities and Exchange Commission filings also show that the compound has the generic name oxycodegol.
In line with the newer timeframe, Nektar announced the formation of a new CNS-focused subsidiary on 23 May. Inheris Biopharma “will lead all of the preparations for the potential commercialization of NKTR-181, as well as development of other CNS programs,” the company said.
NKTR-181 was created using Nektar’s proprietary polymer conjugate technology, which “provides it with a long-acting profile and slows its entry into the CNS,” the company explains. “The abuse deterrent properties of NKTR-181 are inherent to its novel molecular structure and do not rely on a formulation approach to prevent its conversion into a more abusable form of an opioid.”
The NDA seeks approval of oxycodegol for treatment of chronic low back pain in opioid-naïve adults.
Whatever FDA’s decision on the drug, it will likely be controversial. Public Citizen, for example, has filed a citizen petition calling for a halt to all new opioid approvals. (Also see "Opioids: FDA Actions May Silence Call For Moratorium On Approvals " - Pink Sheet, 26 Mar, 2019.)