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Orphan Drug & Fast Track Designations for PTC596 in Rare Oncology Indications

The FDA has granted PTC596 both Orphan Drug Designation and Fast Track designation for the potential treatment of leiomyosarcoma (LMS), a rare type of cancer that affects smooth muscle tissue. Furthermore, the FDA has also granted PTC596 a Rare Pediatric Disease designation and Orphan Drug Designation for the potential treatment of diffuse intrinsic pontine glioma (DIPG), an ultra-rare childhood glioma. PTC596 is currently being studied in clinical trials in LMS and DIPG.

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PTC596 is an orally bioavailable small-molecule tubulin-binding agent that arrests tumor cells in the G2/M phase, including cancer stem cells, through the action of inhibiting tubulin polymerization. It is currently in a Phase Ib study for LMS, which accounts for approximately 10-28 percent of all soft tissue sarcomas. Approximately 4,000 patients are diagnosed with LMS annually in the U.S., the risk of developing metastases is approximately 40 percent, and the 5-year survival rate is estimated to be 13.6 percent for metastatic LMS.


PTC596 is also currently in a clinical study for DIPG, an ultra-rare glioma arising in the brainstem that makes up 10-15 percent of all brain tumors in children. Approximately 300 patients are diagnosed with DIPG annually in the U.S., and the median overall survival with the current standard of care of radiation therapy is approximately 9 months with a 2-year overall survival rate of less than 10 percent.


Regenerative Medicine Advanced Therapy Designation Granted to AB-205 for Lymphoma Toxicities

The FDA granted the Regenerative Medicine Advanced Therapy designation for AB-205 for "the treatment of organ vascular niche injuries to prevent or reduce severe regimen-related toxicities (SRRT) in patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) undergoing high-dose therapy (HDT) and autologous hematopoietic stem cell transplantation." Based on its Phase II trial results, researchers expect to initiate a single pivotal registration Phase III trial in 2021 involving leading cancer centers in North America and Europe.


HDT and autologous hematopoietic cell transplantation (AHCT) are considered a standard-of-care therapy for patients with aggressive systemic HL and NHL. Although efficacious and considered a potential cure, HDT-AHCT is associated with SRRTs that increase patient morbidity and risk for mortality, especially in the aging population. Effective prevention of SRRT may lead to more patients being eligible for a potential cure through HDT and stem cell transplantation.


The human body is capable of renewing, healing, and restoring organs. For example, the human oral-GI tract renews its lining every 3-7 days. Both the organ renewal and healing processes are dependent on organ stem cell vascular niches made up of stem cells, endothelial cells, and supportive cells.


When tissues are injured, the vascular niche endothelial cells direct the stem cells, via angiocrine factor expression, to repair and restore the damaged tissue. This restorative capacity is most active during childhood and youth, but starts to diminish with increasing age. HDT provided to eradicate cancer cells also cause diffuse, collateral damage to vascular niches of multiple healthy organs. In particular, the organs with the highest cell turnover (ones with most active vascular niches) are severely affected.


Specifically, the oral-GI tract, dependent on constant renewal of its mucosal lining, starts to break down upon vascular niche injury. The mucosal breakdown can cause severe nausea, vomiting, and diarrhea. In addition, the bacteria in the gut may escape into the circulation, resulting in patients becoming ill with endotoxemia, bacteremia, or potentially lethal sepsis. HDT-related vascular niche damage can also occur in other organs resulting in severe or life-threatening complications involving the lung, heart, kidney, or liver. Collectively, these complications are known as severe regimen-related toxicities or SRRT, and can occur as frequently as 50 percent in lymphoma HDT-AHCT patients, with increased rate and severity in older patients.


AB-205 is a first-in-class engineered cell therapy consisting of proprietary "universal" E-CEL (human engineered cord endothelial) cells. The AB-205 cells are intravenously administered after the completion of HDT on the same day as when the patient's own (autologous) blood stem cells are infused. AB-205 acts promptly to repair injured vascular niches of organs damaged by HDT. By repairing the vascular niches, AB-205 restores the natural process of tissue renewal, vital for organs such as oral-GI tract and the bone marrow. Successful and prompt organ restoration can prevent or reduce SRRT, an outcome that is beneficial to quality of life and cost-reductive to the health care system.


FoundationOneLiquid CDx Approved as Companion Diagnostic for Olaparib

The FDA approved FoundationOne Liquid CDx to be used as a companion diagnostic for olaparib. It will use a blood-based biopsy to identify patients with BRCA1, BRCA2, and/or ATM alterations in metastatic castration-resistant prostate cancer (mCRPC) who may be appropriate for treatment with olaparib. The liquid biopsy test was approved by the FDA in August to report genomic alteration results for patients with any solid tumor.


Prostate cancer is the second most common cancer in men globally and, despite progress made toward new treatment modalities, the mortality rate for this condition remains high. Of critical importance is ensuring metastatic prostate cancer patients receive comprehensive genomic profiling via liquid or tissue-based biopsies to determine eligibility for new targeted treatment options like olaparib. FoundationOne CDx, a tissue-based comprehensive genomic profiling test, was approved as a companion diagnostic for olaparib in May 2020. Using a blood sample, the test analyzes over 300 cancer-related genes for genomic alterations. It is now approved as a companion diagnostic for seven targeted therapies across four tumor types.


Olaparib was approved for mCRPC patients who carry mutations in homologous recombination repair (HRR) genes, based on the PROfound study, which was the first positive phase III biomarker-selected study using a molecularly targeted treatment in men with mCRPC. The trial is the largest prospective Phase III study to date performing central tissue testing for HRR gene mutations in mCRPC patients.


As a laboratory professional service which has not been reviewed or approved by the FDA, the FoundationOne Liquid CDx report delivers information about the genomic signature microsatellite instability (MSI) and blood tumor mutational burden, as well as single gene alterations, including NTRK fusions, to help inform the use of other therapies, including immunotherapies. The report also provides relevant clinical trial information and includes interpretive content developed in accordance with professional guidelines in oncology for patients with any solid tumor.


FoundationOne Liquid CDx is a qualitative next-generation sequencing based in vitro diagnostic test for prescription use only that uses targeted high-throughput hybridization-based capture technology to analyze 324 genes utilizing circulating cell-free DNA isolated from plasma derived from anti-coagulated peripheral whole blood of advanced cancer patients. The test is FDA-approved to report short variants in over 300 genes and is a companion diagnostic to identify patients who may benefit from treatment with specific therapies in accordance with the approved therapeutic product labeling.


Additional genomic findings may be reported and are not prescriptive or conclusive for labeled use of any specific therapeutic product. Use of the test does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Patients who are negative for companion diagnostic mutations should be reflexed to tumor tissue testing and mutation status confirmed using an FDA-approved tumor tissue test, if feasible.


FoundationOne CDx is a next-generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations in 324 genes and select gene rearrangements, as well as genomic signatures including MSI and tumor mutational burden using DNA isolated from formalin-fixed paraffin-embedded tumor tissue specimens. The test is intended as a companion diagnostic to identify patients who may benefit from treatment with certain targeted therapies in accordance with their approved therapeutic product labeling.


Additionally, it is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for patients with solid malignant neoplasms. Use of the test does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Some patients may require a biopsy.


FDA Fast Track Designation of Devimistat for Pancreatic Cancer

The FDA has granted Fast Track designation for devimistat as a treatment for metastatic pancreatic cancer.


"Pancreatic cancer is notoriously challenging to treat and long overdue for a new approach," said Philip A. Philip, MD, PhD, FRCP, the Kathryn Cramer, MD, Endowed Chair in Cancer Research and leader of the Gastrointestinal and Neuroendocrine Multidisciplinary Team at the Barbara Ann Karmanos Cancer Institute at Wayne State University. "We have remained hopeful throughout our pancreatic cancer trials, and now with Fast Track designation, our optimism is further fueled. We believe with this designation [that] cancer metabolism is truly being propelled forward, with devimistat at the helm."


Devimistat is a first-in-class clinical lead compound, which targets enzymes involved in cancer cell energy metabolism and located in the mitochondria of cancer cells. It is designed to target the mitochondrial tricarboxylic acid cycle, a process essential to tumor cell multiplication and survival, selectively in cancer cells. Devimistat substantially increases the sensitivity of cancer cells to a diverse range of chemotherapeutic agents. This synergy allows for potential combinations of devimistat with lower doses of these generally toxic drugs to be more effective with lowering a patient's side effects.


Combination with devimistat represents a diverse range of opportunities to substantially improve a patient's benefit in many different cancers. The FDA has given approval to initiate pivotal Phase III clinical trials in pancreatic cancer (AVENGER 500) and acute myeloid leukemia (ARMADA 2000), and has designated devimistat as an orphan drug for the treatment of pancreatic cancer, acute myeloid leukemia, myelodysplastic syndrome, peripheral T-cell lymphoma, Burkitt's lymphoma, and soft tissue sarcoma.


Accelerated Approval of Pembrolizumab for Locally Recurrent Unresectable or Metastatic TNBC

The FDA granted accelerated approval to pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS >=10) as determined by an FDA-approved test. The FDA also approved the PD-L1 IHC 22C3 pharmDx as a companion diagnostic for selecting patients with TNBC for pembrolizumab.


Approval was based on KEYNOTE-355 (NCT02819518), a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally recurrent unresectable or metastatic TNBC, who had not been previously treated with chemotherapy in the metastatic setting. Patients were randomized (2:1) to receive pembrolizumab 200 mg on day 1 every 3 weeks or placebo in combination with different chemotherapy treatments (paclitaxel protein-bound, or paclitaxel, or gemcitabine plus carboplatin) via intravenous infusion.


The main efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent review according to RECIST 1.1, tested in the subgroup of patients with CPS >=10. Median PFS was 9.7 months (95% CI: 7.6, 11.3) in the pembrolizumab plus chemotherapy arm and 5.6 months (95% CI:5.3, 7.5) in the placebo arm (HR 0.65; 95% CI: 0.49, 0.86; one-sided p=0.0012).


The most common adverse reactions (incidence >=20%) in patients receiving pembrolizumab plus chemotherapy in KEYNOTE-355 were fatigue, nausea, diarrhea, constipation, vomiting, alopecia, rash, cough, decreased appetite, and headache. The most common laboratory abnormalities (incidence >=20%) in patients receiving pembrolizumab plus chemotherapy were anemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia, elevated ALT and AST, hyperglycemia, hypoalbuminemia, increased alkaline phosphatase, hypocalcemia, hyponatremia, hypophosphatemia, and hypokalemia.


The recommended pembrolizumab dose for adult patients with locally recurrent unresectable or metastatic TNBC is 200 mg every 3 weeks or 400 mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months. When given with pembrolizumab, either paclitaxel protein bound 100 mg/m2 on days 1, 8, and 15 every 28 days; or paclitaxel 90 mg/m2 on days 1, 8, and 15 every 28 days; or gemcitabine 1,000 mg/m2 plus carboplatin AUC 2 mg/mL/min on days 1 and 8 every 21 days, it is administered via intravenous infusion.


Draft Guidance on Cross Labeling Oncology Drugs in Combination Regimens

The FDA issued a draft guidance on Cross Labeling Oncology Drugs in Combination Regimens Guidance for Industry and requested comments to be submitted by January 19, 2021.


The draft guidance stated: "Drug approvals in oncology often build on treatment effects by adding drugs to current regimens or by combining investigational drug products in a combination regimen, creating new regimens with greater efficacy. Traditionally, applicants have not requested changes to the labeling of a previously approved drug to describe how to use that drug in a new regimen (cross labeling). However, there has recently been an increasing number of applications that have proposed cross labeling for oncology drug combination regimens.


"The purpose of this guidance is to describe FDA's current recommendations about including relevant information in labeling for oncology drugs approved for use in a combination regimen, including important considerations for cross labeling of these drugs. This guidance does not address all issues that might arise relating to labeling for oncology drugs for use in a combination regimen. Applicants proposing cross labeling for oncology drug combination regimens should contact the review division for information on cross labeling of their individual products."