Silas Inman

FDA Authorizations Rapid Point-of-Care SARS-CoV-2 Diagnostic

," was originally published on ContagionLive.

The US Food and Drug Administration (FDA) has granted emergency use authorization to a rapid, point-of-care diagnostic designed to detect COVID-19 infection, according to a 

 released March 21, 2020. The test, labeled Xpert Xpress SARS-CoV-2, was developed by Cepheid to detect SARS-CoV-2 in approximately 45 minutes, following specimen collection from a nasopharyngeal swab and nasal wash or aspirate. Cepheid plans to begin shipping the test by March 30.

“Our dedicated team at the FDA has been working nonstop to expedite the review and authorization of novel diagnostics during the COVID-19 public health emergency,” Stephen Hahn, MD, FDA Commissioner, said in a statement. “Today marks an important step in expanding the availability of testing and, importantly, rapid results. Point-of-care testing means that results are delivered to patients in the patient care settings, like hospitals, urgent care centers and emergency rooms, instead of samples being sent to a laboratory. With today’s authorization, there is now an option for testing at the point of care, which enables patient access to more immediate results.”

The Xpert Xpress SARS-CoV-2 test cartridge is designed to detect nucleic acid from SARS-CoV-2 via real-time polymerase chain reaction. The cartridge contains a complete solution and does not require the use of reagents, according to 

 available from the company. The GeneXpert System is required to run the test in a CLIA-approved laboratory or select patient care settings.  

"Cepheid currently has nearly 5000 GeneXpert Systems in the US capable of point-of-care testing and for use in hospitals," Warren Kocmond, president of Cepheid, said in a 

. "Our automated systems do not require users to have specialty training to perform testing, they are capable of running 24/7, with many systems already doing so today."

The FDA's emergency use authorization program allows unapproved products to be used in the context of a public health crisis, such as the SARS-CoV-2 pandemic. A number of other diagnostics have already gained emergency use authorization; however, the Xpert Xpress SARS-CoV-2 test is the first point-of-care option.

“With the development of point of care diagnostics, Americans who need tests will be able to get results faster than ever before. More and more options for reliable, convenient testing are becoming available at an incredibly rapid pace, thanks to the hard work of our FDA team and the ingenuity of American industry," said Alex Azar, HHS Secretary. "With new tools like point-of-care diagnostics, we are moving into a new phase of testing, where tests will be much more easily accessible to Americans who need them.”

At the time of the FDA's authorization, there were over 300,000 globally reported confirmed cases of COVID-19, with the number rapidly growing in the United States to beyond 24,000. Diagnostics, as well as personal protective equipment, remain an ongoing challenge in the fight against the coronavirus.

"During this time of increased demand for hospital services, Clinicians urgently need an on-demand diagnostic test for real-time management of patients being evaluated for admission to health-care facilities," David Persing, MD, PhD, chief medical and technology officer at Cepheid, said in a statement. "An accurate test delivered close to the patient can be transformative and help alleviate the pressure that the emergence of the 2019-nCoV outbreak has put on healthcare facilities that need to properly allocate their respiratory isolation resources."

For the most recent case counts in the COVID-19 outbreak, check out the 

Articles

FDA grants emergency use authorization to a rapid point-of-care test to detect COVID-19 infection.

Point-of-Care COVID-19 Test Gets FDA Authorization

Adding the novel small molecule inhibitor navitoclax to ongoing treatment with standard of care ruxolitinib (Jakafi) resulted in clinically meaningful reduction in spleen size and improvements in symptoms for patients with primary or secondary myelofibrosis, including those with resistance to ruxolitinib alone, according to findings from a phase II study presented at the 2019 ASH Annual Meeting.

Forty-three percent of patients achieved a spleen volume response of ≥35% (SVR35) with the combination of navitoclax and rituximab during the study. Additionally, 25% of patients saw a reduction in bone marrow fibrosis compared with baseline. There was a 1-grade reduction in fibrosis for 13% of patients and a 2-grade improvement for an additional 13% of patients. Sixty-five percent of patients experienced a reduction in symptoms, and 35% of patients experienced a ≥50% reduction in total symptom score (TSS).

"Encouraging reductions in bone marrow fibrosis were observed, and navitoclax in combination with ruxolitinib was well tolerated,” Jacqueline S. Garcia, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, said during a presentation of the findings. "The addition of navitoclax overcomes resistance in patients with uncontrolled myelofibrosis, despite prior prolonged ruxolitinib exposure."

The phase II study enrolled 34 patients with primary myelofibrosis (n = 16), post-essential thrombocythemia myelofibrosis (n = 5), and post-polycythemia vera myelofibrosis (n = 13). All patients had received ruxolitinib for ≥12 weeks prior to first dose of navitoclax, with no washout period prior to the start of the trial. The dose of navitoclax was escalated from 50 mg daily to 300 mg daily over the course of the study. 

Of those available for baseline testing, more than half had high molecular risk (52%). The most common mutations identified were 

 (21%). Overall, 47% of patients at high-risk had 2 or more mutations. The duration of prior ruxolitinib therapy was 21 months (range, 4-71) and the baseline spleen volume was 1665 cm

At week 24, SVR35 was achieved by 30% of patients with the combination of navitoclax and rituximab. Additionally, 53% of patients had resolution of palpable splenomegaly.

The mean white blood cell count at week 24 was 25.8 x 10

/L. Two patients entered the study with transplant dependence, with 1 becoming transplant independent following the addition of navitoclax. Seven patients entered the study receiving ≥1 unit of packed red blood cells within the past 12 weeks. Of these patients, 57% were transplant-free for ≥12 weeks following treatment with the combination. Platelet counts stabilized during the study, going from 232 x 10

"Although very early transient thrombocytopenia was observed immediately after dosing, as expected, it was manageable with a slow weekly dosing ramp up," said Garcia. "The time frame of the 8-week nadir is similar to what we initially observed with ruxolitinib alone."

The median duration of navitoclax treatment was 330 days, and 68% were able to achieve the maximum tolerated dose of 300 mg. Most patients entered the trial on ruxolitinib doses >10 mg twice daily (BID) but most were able to reduce their dose to 10 mg BID during the study (88%).

A quarter of patients discontinued navitoclax during the study (27%), due to adverse events (AEs; 9%), progressive disease (6%), and other causes (12%). Grade ≥3 AEs of any cause were experienced by 79% of patients receiving the combination. The most common grade ≥3 AEs were thrombocytopenia (44%), anemia (27%), diarrhea (6%), and vomiting (3%). Eight patients experienced a serious AE (24%). There was 1 grade 5 case of pneumonia that was deemed unrelated to navitoclax.

The phase II study is still ongoing to further assess navitoclax alone or in combination with ruxolitinib for patients with myelofibrosis (NCT03222609). Additionally, outside of the United States, an expanded access program is available to gain access to navitoclax (NCT03592576).

Harrison CN, Garcia JS, Mesa JA, et al. Results from a Phase 2 Study of Navitoclax in Combination with Ruxolitinib in Patients with Primary or Secondary Myelofibrosis. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 671.

Results of a recent study from ASH 2019 is suggesting a combination of navitoclax and ruxolitinib could improve outcomes for patients with myelofibrosis. 

Navitoclax/Ruxolitinib Combination Improves Outcomes for Patients With Myelofibrosis

The novel BET inhibitor CPI-0610 was effectively added to standard of care ruxolitinib (Jakafi) for patients with advanced myelofibrosis, with almost half of patients capable of stopping regular blood transfusions for their disease at a 24-week analysis, according to updated findings from the phase II MANIFEST trial presented at the 2019 ASH Annual Meeting.

The addition of CPI-0610 to ongoing treatment with ruxolitinib, resulted in a 24.9% reduction in spleen volume at 24 weeks and a 58.8% improvement in total symptom score (TSS) for transfusion dependent (TD) patients with myelofibrosis. Additionally, 43% of patients converted from being TD to transfusion independent (TI) following treatment with the combination.

"Among evaluable patients who were transfusion dependent on ruxolitinib, 6 of 14 patients converted to transfusion independence after the addition of CPl-0610 in the study,” John Mascarenhas, MD, Tisch Cancer Institute, Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, said during a presentation of the results. “Symptom responses were seen in a majority of patients, we know this because they told us, we treated these patients and they did much better.”

The MANIFEST trial included multiple treatment arms, each looking at cohorts of TD and TI patients. Arm 1 of the study examined single-agent CPI-0610 following prior treatment with ruxolitinib (n = 36). In arm 2 of the study, CPI-0610 was added to ruxolitinib for patients already receiving the JAK/STAT inhibitor for at least 6 months (n = 54). Arm 1 of the study included cohort 1A, in which patients were TD. Cohort 1B within this same group included those who were TI. In arm 2, patients included in cohort 2A of this group were TD and cohort 2B were TI.

Of those who transitioned from TD to TI, 36.4% in the combination arm had bone marrow improvement. A 1 grade improvement in bone marrow fibrosis was seen in 38% of patients analyzed, with most of these occurring within 6 months of treatment (83%).

Across both groups, 83.3% of patients continued on the study at the time of the analysis. The primary reason for discontinuation was progressive disease (5.6%) or death (5.6%). The median treatment duration was 16.2 weeks, and 41.1% of patients have been on treatment for 24 weeks or longer.

In arm 2 looking at CPI-0610 added to ruxolitinib, a spleen volume response with at least 35% reduction in spleen size (SVR35) at week 24 was experienced by 25% of TD patients. Additionally, a TSS reduction of ≥50% (TSS50) at week 24 was experienced by 54% of TD patients. Seventy-five percent of patients noted an improvement in overall status by patient global impression of change (PGIC) scores. In TI patients treated with the combination, the SVR35 rate was 0 and the TSS ≥50% response was 38% at 24 weeks. In this group, there was a 69% improvement in PGIC score, with 46% of patients saying their overall status was much or very much improved.

In arm 1 looking at CPI-0610 monotherapy, the SVR35 was 0 and there was a median reduction in spleen size of 3.2% in TD patients. TSS ≥50% was 0 with the single agent, with a mean reduction from baseline of 18.4%. The PGIC score improved by 50%. In TI patients in arm 1, the SVR35 was 0 and the median change in spleen reduction was 26%. TSS ≥50% occurred in 60% of patients, with a median reduction of 53.5%. At 24 weeks, there was a 100% improvement in PGIC scores, with more than half of patients saying they were much improved (57%).

In the monotherapy and combination groups, respectively, 55% and 13% of patients had improvements of ≥1.5 g/dL in hemoglobin counts. Bone marrow fibrosis was improved from baseline to subsequent bone marrow biopsy for 22.2% and 43.5% of patients in the monotherapy and combination groups, respectively. Both hemoglobin and bone marrow fibrosis improvements were seen in 22.2% and 17.4% of patients, in the single-agent and combination arms, respectively.

The most common all-grade, all-cause adverse events (AEs) were diarrhea (32.2%), thrombocytopenia (23.3%), nausea (22.2%), cough (16.7%), vomiting (14.4%), fatigue (14.4%), and upper respiratory tract infection (14.4%). Non-hematologic AEs were primary grade 1/2 in severity, Mascarenhas noted.

The most common grade ≥3 AEs were thrombocytopenia (10%), anemia (6.7%), diarrhea (4.4%), and fatigue (3.3%). None of the grade ≥3 cases of thrombocytopenia were deemed serious, Mascarenhas noted. Across the 90 patients enrolled in the study, 8 experienced a grade 4 AE (8.9%). There were 3 grade 5 events (3.3%), which were not considered related to CPI-0610. These events all occurred in arm 2 of the study.

"CPl-0610 as monotherapy and as add-on was generally well tolerated. Thrombocytopenia was observed and asymptomatic. It was generally reversible and manageable and there were no additional unanticipated safety concerns observed," said Mascarenhas.

Based on findings from the first arms of the study, cohort 2A was expanded to enroll an additional 60 patients for the combination of CPl-0610 and ruxolitinib. Additionally, arm 3 of the study, which was not presented as part of this presentation, is looking at the combination of CPI-0610 with ruxolitinib in untreated patients with myelofibrosis. Based on these preliminary findings, cohort 3 of the study is being expanded to enroll up to 101 patients (NCT02158858).

Mascarenhas J, Kremyanskaya M, Hoffman R, et al. 

MANIFEST, a Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Domain Inhibitor (BETi), As Monotherapy or “Add-on” to Ruxolitinib, in Patients with Refractory or Intolerant Advanced Myelofibrosis

. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 670.

Results of the phase 2 MANIFEST study presented at ASH 2019 suggest CPI-0610 could be an effective treatment for patients with refractory or intolerant advanced myelofibrosis. 

Novel Agent Shows Early Promise for Advanced Myelofibrosis

The rAAV2/2-ND4 gene therapy GS010 elicited continuous bilateral improvements in BCVA from week 48 to week 96 for patients with Leber hereditary optic neuropathy (LHON), according to findings from the phase 3 RESCUE trial presentation at the 

2019 American Academy of Ophthalmology Annual Meeting

Following enrollment in the trial, vision continued to decline until it reached its lowest level at week 48. In the GS010 arm, the lowest BCVA was 1.918 LogMAR and in the fellow-eye sham group it was 1.908 LogMAR. By week 96, there was a 26.3 letters improvement in BCVA in the gene therapy arm compared with 22.8 letters in the sham group. The primary endpoint of the study, which was a 15-letter difference between the GS010 and the sham group, was not met.

"There is a bilateral improvement in both the treated and untreated eyes, which was unexpected," said lead investigator Patrick Yu-Wai-Man, MBBS, PhD, from the University of Cambridge. "The change from the nadir at 48 weeks was 26 letters in the treated eye and 23 letters in the sham eye, which is a significant improvement in vision."

The change in both eyes confounded the endpoint and was unexpected, Yu-Wai-Man noted. To help uncover potential reasons for this, researchers conducted a second analysis looking at unilateral intravitreal injections of the gene therapy in non-human primates.

For the study, 3 non-human primates received unilateral treatment in their right eyes. There was one control animal. Tissue was sampled 3 months after injection. At the 3-month analysis, viral vector DNA was detected in all tissues, except the tears. The viral vector DNA was also detected in the contralateral optic nerve.

"There is evidence of transfer of viral vector DNA from the injected eye to the contralateral uninfected eye," said Yu-Wai-Man. "This provides a plausible explanation for the unexpected bilateral improvement." 

The phase 3 RESCUE trial enrolled 39 patients with LHON at a mean age of 36.8 years. Data were available for 73 eyes for vision loss duration (VLD), with a mean VLD of 112.1 days. BCVA was available for 76 eyes, with a mean BCVA of 1.29 LogMAR, which is below the legal definition of blindness in the United Kingdom (<1.30). Findings in the treated eye were compared with the fellow eye, which received a sham therapy.

Over the course of the study, there was a -0.526 LogMAR change in BCVA in the GS010 gene therapy group by week 96. In the sham eyes, there was a -0.457 LogMAR change from baseline to week 96.

Clinically relevant recover (CRR) at week 96 was also measured, defined as improvement of ≥10 letters read for eyes on chart and at least 5 letters read for those off chart. In the GS010 group, 63.2% of patients experienced a CRR. When compared with retrospective studies looking at the natural history of LHON, only 27.9% of patients had a CRR in at least 1 year, suggesting a benefit with the gene therapy.

Similar findings were experienced in the REVERSE trial, which was a separate phase 3 study that also explored GS010 for LHON. This trial explored the treatment in 37 patients who were more than 181 to 365 das from the onset of disease. The initial BCVA at the start of the trial was 1.61 LogMAR. Similar treatment trends and differences were observed in this trial, including a bilateral improvement in BCVA.

Given the clinical benefit seen in both studies, GenSight Biologics, the company developing GS010, plans to enter conversations with regulatory agencies. The company hopes to file for approval in Europe in the third quarter of 2020.

Yu-Wai-Man P, Moster M, Sadun A, et al. Efficacy of rAAV2/2-ND4 Gene Therapy for Leber Hereditary Optic Neuropathy: 96-Week Data From the Phase 3 RESCUE Trial. Presented at: 2019 AAO Annual Meeting, San Francisco, CA, October 12-15, 2019. PA021.

The rAAV2/2-ND4 gene therapy GS010 elicited continuous bilateral improvements in BCVA from week 48 to week 96 for patients with Leber hereditary optic neuropathy.