Three companies are looking for decisions by the U.S. Food and Drug Administration (FDA) this week. All three drugs are either resubmissions or have had to deal with various problems related to manufacturing or incomplete data. Here’s a look.
Evoke Pharma’s Gimoti Runs Into Trouble
Evoke Pharma’s Gimoti has a target action date of April 1. On March 4, the Solana Beach, Calif.-based company received a multi-disciplinary review (DR) letter from the FDA in association with its New Drug Application (NDA) for Gimotti. A DR letter is used by the FDA to communicate its early thinking on deficiencies observed in an initial review of an NDA. Gimotti is designed to treat gastroparesis, a debilitating, episodic condition characterized by slow or delayed gastric emptying of the stomach after meals, often resulting in symptom flare-ups that include nausea, vomiting, abdominal pain and bloating. It occurs disproportionately in adult women.
There were three sections of the NDA that the agency had concerns about. They were chemistry, a combination of product quality control and reproducibility connected to the commercially available sprayer device used with the drug; clinical—lack of enough data to support sex-based efficacy differences; and clinical pharmacology, specifically that the maximum concentration wasn’t within the parameters of the bioequivalence for abbreviated NDAs.
In theory, the DR letter doesn’t reflect a final FDA decision, but it does throw the April 1 target action date into a cloud of uncertainty.
On March 14, Evoke submitted a response to the DR and requested a meeting with the agency over the April 1 target action date. The meeting was held on March 21, but at this time no information has been released about the content of that meeting.
IntelGenx’s Rizaport for Acute Migraine
Saint Laurent, Quebec-based IntelGenx Corp. has an April 1 target action date for the resubmitted NDA for Rizaport, a VersaFilm oral soluble film to treat acute migraines. The company has five inspectional observations from a January Pre-Approval Inspection as part of the company’s Health Canada-certified cGMP manufacturing facility in Montreal by the FDA. At the time, Horst G. Zerbe, president and chief executive officer of IntelGenx said, “We appreciate the thoroughness of the FDA’s review of our facility, and we are confident that we will be able to address the FDA’s observations within the 15-day response timeframe.” As we continue to advance through the NDA process, IntelGenx is excited to have completed another important milestone toward U.S. approval.”
Rizaport is a proprietary oral thin film formulation of rizatriptan benzoate, a 5-HT1 receptor agonist and the active drug in Merck & Co.’s Maxalt.
ADMA Biologics’ Resubmission of Bivigam
ADMA Biologics, headquartered in Ramsey, NJ, has a target action date of April 2 for Bivigam for the treatment of Primary Immunodeficiency Disease (PIDD). PIDD is a class of inherited genetic diseases that result in a deficient or absent immune system. The FDA issued a Complete Response Letter (CRL) on December 19, 2018 for Bivigam. On January 7, 2019, ADMA submitted its response and provided supplemental information.
Bivigam is an intravenous immune globulin indicated for the treatment of primary humoral immunodeficiency. That includes agammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome and severe combined immunodeficiency. Bivigam holds a broad range of antibodies similar to those observed in normal human plasma. The antibodies are directed against bacteria and viruses, and help protect PIDD patients against serious infections.
https://www.biospace.com/article/fda-action-alert-evoke-pharma-intelgenx-and-adma-biologics/
Sunday, March 31, 2019
Opioid Crisis: Action News investigates safe injection sites
Safe injection sites are places for opioid addicts to go use their drugs in a controlled environment.
There is a push to bring such sites to Philadelphia, but not everyone is on board with the idea. So Action News traveled to Toronto, Canada where safe injection sites are already up and running to get a first-hand look.
We found a mixed reaction.
There are still many hurdles before they become reality here in Philly, but they’ll be largely modeled after sites in Canada.
There’s no question these sites save lives and prevent disease, but their location can create concern from residents. We met Farrah Morrison in one of those sites. She was getting a fix with a clean needle inside a sterile room, all while being monitored in case of an overdose.
“You cannot use alone because you will die,” she said. “You will die.”
It’s been nearly a year since Toronto opened its first federally approved safe injection site.
“We offer all the supplies that they’d need: tourniquet, sterile water, cookers, and then they can select the needle that most meets their needs,” said Shaun Hopkins, who runs a site in the heart of Toronto’s tourism district. “We intervened, so far, from August 2017, in about 170 overdoses either with Naloxone or oxygen. So you could say we’ve saved those lives,” she said.
In Toronto, roughly 300 people died from an opioid-related overdose in 2017. Not one of those deaths happened in one of these facilities. Naloxone, commonly known by the brand name Narcan, is readily available. After a user injects, they’re urged to go to an observation room.
When asked about public support for the facility, and whether it has increased or decreased, Hopkins said, “I think public support for this facility is difficult.”
And this is why: Over the two days we sat outside several of Toronto’s safe injection facilities, we witnessed prevalent drug use out front, drug deals, and even violence. We watched as one man harassed several people passing by on the sidewalk, even putting one in a chokehold. One guy decided to fight back and security arrived.
Christine Wittick owns the Football Factory, a bar neighboring one of the city’s half-dozen operational safe injection sites. She understands the need, but feels the rights of the addicts often come before those in the community.
“We started to have drug dealers and prostitutes across the street. Crime started to escalate, neighbors have had their homes broken into, my husband has been punched in the face by a man who was very, very high in front of customers,” Wittick said.
In Moss Park, we met a woman named April. Like many users, she’s addicted to both crack and heroin. We found her using just a few hundred feet from a supervised injection site.
“I go and get a lot of supplies and don’t stick around,” she said. April admits that the site attracted more users and dealers, but said the impact is worth it to save lives.
“If you use alone, you die alone,” she said. “You’ve got to weigh the negative with the positive. Saving a life is a lot more important that the other things that come along with it.”
Bill Coldin lives across the street from the park. He admits there was drug usage there before the facility opened last year, but says it’s increased since. We asked: What would your message be to Philadelphians?
“Be careful where you put them,” he said. “You are going to need increased policing around them.”
He says the site in his neighborhood is not being used for its intended purpose.
“What bothers me is no one is using is the facility. And if they are using it, they are using it to socialize and talk right there,” said Coldin.
Toronto City Councilor Giorgio Mammoliti is an outspoken critic of the safe injection sites. He believes the facilities should be placed in hospitals and have a greater emphasis on treatment. But Canadian health officials say you can’t push addicts into treatment.
If you do, they say, addicts won’t use the sites. First, they say, trust needs to be established and it’s inside these walls where that will happen.
Here in Philadelphia, city leaders have been selling the public on the idea that so-called comprehensive user engagement sites will be a bridge to rehab.
“Every city is going to address this in a different way. We believe strongly in getting people in treatment is our goal, and pushing that at every step in the process,” said Philadelphia Health Commissioner Tom Farley.
Farley said he hopes to open a supervised injection site within the year, but says the biggest obstacles are the legal issues and whether the United States Attorney General’s office will take action if one opens.
Research on the effectiveness of supervised injection sites being a path to treatment have been inconclusive. Toronto was unable to provide any statistics regarding its sites. However, the city of Vancouver’s original facility, Insite, reports out of 7,300 users in 2017, just six percent accessed its detox treatment facility, and the average stay was just 11 days.
After shooting up her latest hit, Farrah Morrison said she was ready to get off drugs and connect with her three children. She’s using this site as the road to that recovery, but where it ends is unclear.
“Wish me luck,” she said.
CD40 antibody combination therapy can shrink pancreatic tumors
A new combination of immunotherapy and chemotherapy for pancreatic cancer caused tumors to shrink in the majority of evaluable patients—20 out of 24 as of an interim analysis of the phase 1b trial data. The early findings provide hope that this strategy involving a CD40 antibody, a checkpoint inhibitor, and standard-of-care chemotherapy could be effective for treating the nation’s third deadliest type of cancer. Researchers from the Abramson Cancer Center at the University of Pennsylvania will present the findings today in a clinical trials plenary session at the American Association for Cancer Research 2019 Annual Meeting in Atlanta (Abstract #8060). The ongoing study is being conducted in collaboration with the Parker Institute for Cancer Immunotherapy and its other member institutions and partners. These are the first clinical trial data ever presented as a result of this collaboration.
“These findings give us clues that this new and innovative combination therapy can be effective against pancreatic cancer,” said the study’s co-lead author Mark H. O’Hara, MD, an assistant professor of Hematology-Oncology at Penn. “Although only time and further research will truly tell, our data are a reason for optimism.” O’Hara will present the plenary at 12:45 p.m. in Marcus Auditorium, Bldg A-GWCC.
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it kills more Americans each year than any cancer type other than lung and colorectal. Despite the fact that it only accounts for about three percent of new cancer cases, it is responsible for more than seven percent of all cancer deaths, and just 8.5 percent of patients survive five years with the disease. Previous research has shown PD-1 inhibitors are ineffective on their own against PDAC, but preclinical data showed combining PD-1 inhibitors with antibodies that target a different antigen known as CD40 can trigger an immune response.
For this study, patients with metastatic PDAC who were previously untreated received combinations of four different therapies. Each patient received gemcitabine and nab-paclitaxel, which are standard-of-care chemotherapies, as well as an experimental antibody targeting CD40 called APX005M. Half the patients also received the PD-1 inhibitor nivolumab. As of the data cutoff for the interim analysis, 20 of 24 patients (83 percent) saw their tumors shrink. Overall, although the majority of the patients experienced side effects from the treatment, they were expected and manageable, with several patients continuing on treatment for more than a year, which also suggests the combination treatment can produce a durable response.
“Seeing patients continue treatment for this length of time does give us hope that this combination approach holds promise, especially when you consider that for stage 4 pancreatic cancer, the median survival is just two to six months,” said senior author Robert H. Vonderheide, MD, DPhil, director of the Abramson Cancer Center and a Parker Institute member researcher. Vonderheide previously led the first-in-human clinical trial of APX005M reported in 2017 that enabled the current study.
The Parker Institute holds the Investigational New Drug application from the U.S. Federal Drug Administration. Patients on this trial were treated at seven Parker member institutions, leveraging a unique ability to develop faster and more efficient clinical studies.
“This study represents the first illustration that our unique collaborative model, which we used to bring together partners from across academia, pharma, and biotech, can help speed the process of translating laboratory findings into efficient, impactful clinical trials in areas with high unmet medical need,” said Ramy Ibrahim, MD, the chief medical officer at the Parker Institute for Cancer Immunotherapy. “Based on these early but promising findings, we are excited to see results from the next phase of the study.”
In addition to Penn, Parker member institutions who treated patients on this study were Memorial Sloan Kettering Cancer Center; The University of Texas MD Anderson Cancer Center; University of California, Los Angeles; University of California, San Francisco; Stanford University; and Dana-Farber Cancer Institute.
The randomized phase two portion of the trial evaluating chemotherapy, APX005M, and/or nivolumab is currently underway. Apexigen, which manufactures APX005M, and Bristol-Myers Squibb, which manufactures nivolumab, each supplied the drugs for this study. Additional support was provided by the Cancer Research Institute.
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Bristol-Myers Squibb’s Opdivo-Yervoy duo provokes response in rare tumors
Bristol-Myers Squibb has found success with its Opdivo-Yervoy combo in treating various common tumors. But it turns out the duo can help some patients with rare tumors, too.
Sunday at the American Association for Cancer Research annual meeting, researchers unveiled data from an investigator-sponsored phase 2 study showing that Opdivo and Yervoy could produce a benefit in patients with neuroendocrine tumors in various parts of the body.
In a study of 33 patients, 24% responded to therapy, with one patient’s cancer disappearing completely. But among patients with high-grade cancer cells—which tend to grow and spread more quickly—response figures were higher: 42%, or 8 of 19 patients, recorded a response to the combo, while none of the patients with low- or intermediate-grade cancer did.
Based on those numbers, researchers concluded that ”further investigation of this combination is warranted,” they said in the study abstract. And meanwhile, they have an idea as to why the BMS pairing only turned up a benefit in high-grade patients.
“One preliminary hypothesis for this finding is that high-grade neuroendocrine carcinomas may have a higher tumor mutational burden, which is an indicator of better response to immunotherapy,” lead study investigator Sandip Patle, M.D., said in a statement.
Bristol-Myers itself has been working to prove the link between TMB and Opdivo-Yervoy efficacy as it chases an indication in previously untreated non-small cell lung cancer, which is considered immuno-oncology’s largest market. After trumpeting positive data at last year’s AACR meeting, the company last October acknowledged that in a new analysis, the combo’s survival benefit in patients with high TMB and low TMB appeared “quite similar (based on hazard ratios compared to chemotherapy),” as Credit Suisse analyst Vamil Divan put it.
“This leads us to wonder why regulators would approve the regimen strictly for patients with high TMB as per the current filing,” he wrote at the time. And Bristol didn’t wait to find out: It pulled its application in January, citing a need for more data.
Meanwhile, though, Patel and his colleagues say they’ve already scored with the study. “Our study highlights the feasibility of performing clinical trials among patients with rare cancers,” he said, noting that rare tumor types represent “nearly a quarter of all cancers.”
The study will “hopefully will help dispel the belief that clinical trials are not feasible for this patient population,” he added.
#AACR: Neon Therapeutics trial shows benefit in melanoma vaccine
Post-Vaccine Immune and Pathologic Markers Associated with Durable Clinical Benefit in Metastatic Melanoma Patient Cohort
Top-line Results, Including 52-Week Clinical Outcomes, from Full NT-001 Trial in Melanoma, Non-Small Cell Lung and Bladder Cancers Expected Later in 1H 2019
Neon Therapeutics, Inc. (Nasdaq: NTGN), a clinical-stage immuno-oncology company developing neoantigen-based therapeutics, today presented updated data describing the immune and pathologic markers associated with durable clinical benefit in patients enrolled in NT-001, an ongoing Phase 1b clinical trial evaluating NEO-PV-01 in combination with nivolumab (OPDIVO® or anti-PD-1 therapy). The data were highlighted in an oral presentation titled, “The Personalized Vaccine, NEO-PV-01 with Anti-PD-1, Induces Neoantigen-Specific De Novo Immune Responses in Patients with Advanced or Metastatic Melanoma: Association with Clinical Outcomes,” at the American Association for Cancer Research (AACR) Annual Meeting in Atlanta.
NEO-PV-01 is a personal neoantigen vaccine custom-designed and manufactured based on the neoantigens identified by Neon’s proprietary bioinformatics engine, RECON®, as being the most therapeutically relevant for an individual patient. The data presented today, which reflect a cutoff date of August 31, 2018, include 23 patients with metastatic melanoma who received at least one dose of NEO-PV-01 and who either remained progression-free or had progressed by week 36 after the initiation of anti-PD-1 therapy. Patients who did not progress by 36 weeks were classified as having durable clinical benefit (DCB). The data indicate that RECON-based prediction of neoantigen quality correlates with DCB and serves as clinical validation for RECON’s ability to identify therapeutically relevant neoantigens.
“Our new analysis has shown two post-vaccine markers, epitope spread and tumor pathology, that clearly associate with durable clinical benefit. Of the patients tested, we observed epitope spread – which is a cascade of neoantigen recognition beyond those included in the vaccine – in all patients with DCB. Furthermore, the majority of patients with DCB displayed marked reductions in tumor content only after vaccination. We are encouraged by these associations and look forward to evaluating patient outcomes, including clinical responses and progression-free survival, in the more mature 52-week topline data set expected mid-year,” said Richard Gaynor, M.D., President of Research and Development at Neon Therapeutics.
#AACR: Positive Data From Astra, Hutchison China Cancer Drug Trial
Interim results from a phase 1 clinical trial, titled Patton, show that Savolitinib combined with an already-approved medicine, Tagrisso, yielded positive results.
Savolitinib is an investigational therapy under development by AstraZeneca in partnership with Hutchison China MediTech.
Data presented at the 2019 annual American Association for Cancer Research meeting showed that lung cancer patients are responding to the combined treatment.
The study looked at the effect of Savolitinib and Tagrisso in patients with non-small cell lung cancer with a mutation in the EGFR gene.
The objective response rate of the drug combination–a measure of how many patients see a reduction in tumor size–ranged from between 28% and 52%, based on what therapies they had previously undergone.
Dr. Lecia Sequist, who presented the results, said the findings show the benefit of adding a MET inhibitor–the class of drug to which Savolitinib belongs–to already established therapies like Tagrisso in patients whose cancer has acquired drug resistance.
However, she cautioned that this is still early-stage data and the findings need to be confirmed in larger trials.
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