FDA OKs Loxo in 2nd ‘breakthrough’ in tissue-agnostic cancer therapy

Three months ago at ASCO, Loxo Oncology wowed the crowd at the big cancer conference with some early-stage data for its second genetically targeted cancer drug candidate. Today, the biotech announced that the FDA seems similarly impressed, offering a breakthrough drug designation to shorten the regulatory timeline just as Loxo has hoped.

In the interim Phase I/II snapshot provided at ASCO, LOXO-292 spurred a 77% overall response rate for RET fusion-positive cases, the majority of which belonged to the non-small cell lung cancer. In RET-mutant medullary thyroid cancer the rate dropped to 45%.
Correspondingly, the BTD was granted for the treatment of two types of patients, both heavily pretreated: those with metastatic RET-fusion-positive non-small cell lung cancer who require systemic therapy and have progressed following chemo and checkpoint therapies; and those with RET-mutant medullary thyroid cancer needing systemic therapy who have progressed following prior treatment without any alternatives.

Stamford, CT-based Loxo $LOXO is one of the trailblazers in personalized cancer therapies, where patients are grouped no by the site of tumor development but by genetics — an approach that calls for broader sequencing to ID the genetic mutations underpinning each patients’ cancer.

Following a game plan that has catapulted larotrectinib to the final run-up of a widely expected approval in November, Loxo says it will design the next steps in clinical development based on feedback from regulators worldwide — with the final plan expected in 2019.

“We look forward to working with FDA to streamline the development of LOXO-292 in the two patient populations that have comprised the bulk of our initial clinical trial enrollment,” said Josh Bilenker. “Given the many available therapies for non-small cell lung cancer and medullary thyroid cancer, we are pleased that LOXO-292 has shown encouraging data in refractory patients, and hope to demonstrate the full potential of this treatment in additional populations over time.”

https://endpts.com/fda-waves-loxo-through-for-second-breakthrough-in-tissue-agnostic-cancer-therapy/

Eyeing IPO, Fulcrum nails $80M round on way to clinic with 1st gene-regulating med

hat there’s more and more money chasing good science, Fulcrum Therapeutics has grabbed an $80 million B round to back its move into the clinic with the first of its gene regulating small molecules. And the executive team has already blueprinted an IPO for early next year to keep the work progressing at full steam.

“The rounds are getting bigger and bigger,” acknowledges CEO — and longtime biotech veteran — Bob Gould, who offered an update on the company in advance of this latest round. And as the science gets better, fully funded companies like Fulcrum are expected to move faster and faster.

Two years after launching the company, says Gould, they already have 11 clinical sites lined up to start testing their first therapy. And now they can start expanding their clinical development team to help hurry things along.
What used to take 5, 6 or 7 years in biotech, he notes, can now be wrapped in 2.5 to 3 years.

That’s good news for patients suffering from facioscapulohumeral muscular dystrophy (FSHD). Fulcrum has positioned their FSHD drug for the first clinical test, with plans to build up a pipeline behind it focused on rare, genetically based neuromuscular, central nervous system and hematologic disorders.

Advances in genetics have pointed Fulcrum’s team straight at 86 misregulated genes behind FSHD. And Gould says that they can build on the targeting improvements made in oncology to bore right in, asking that specificity question right off the bat. It’s keeping the preclinical work at the Third Rock startup clearly focused.

This new syndicate includes some notable crossover and Chinese investors, pointing me to the IPO question.

Foresite Capital led the round with participation by Fidelity Management and Research Company, 6 Dimensions Capital, Casdin Capital, Sanofi Ventures, Section 32, NS Investments, entities affiliated with Leerink Partners, and undisclosed institutional investors. Foresite’s Jim Tananbaum is joining the board.

They’re all behind a plan to go public next year, says Gould, so long as market conditions remain sunny with clear sailing for IPOs. That’s not in their control. That IPO can come as early as Q1 2019, says Gould, the former Epizyme CEO who’s no stranger to public markets.

https://endpts.com/eyeing-an-ipo-fulcrum-execs-nail-down-an-80m-round-on-the-way-to-the-clinic-with-their-first-gene-regulating-drug/

Court Orders FDA to Move Forward With Graphic Cigarette Warnings

A federal court has ordered the FDA to move forward by the end of the month to issue a final rule requiring graphic health warnings on cigarette packs and advertising.

On Wednesday, Judge Indira Talwani, of the U.S. District Court for the District of Massachusetts, ruled in favor of a lawsuit filed by the American Academy of Pediatrics, the American Lung Association, and six other public health and medical groups contending that the FDA had “unreasonably delayed” and “unlawfully withheld” the final rule on graphic labels, which were originally mandated close to a decade ago.

The judge gave the agency 3 weeks to come up with a plan.

“The court orders that, no later than September 26, 2018, the FDA shall provide to this court an expedited schedule for the completion of outstanding studies, the publication of the proposed graphic warnings rule for public comment, review of public comments, and issuance of a final graphic warning rule in accordance with the Tobacco Control Act,” the ruling stated.

The plaintiffs in the case will then have 2 weeks to submit a response to the proposed schedule.

The 2009 Family Smoking Prevention and Tobacco Control Act, which regulated cigarettes, called for graphic warnings covering the top half of the front and backs of cigarette packs and 20% of cigarette advertising. The FDA was originally given until June of 2011 to issue a final rule requiring the warnings.

The FDA met the initial deadline, but tobacco companies filed lawsuits and the graphic warnings were struck down in August of 2012 by a three-judge panel of the U.S. Court of Appeals for the D.C. Circuit, which ruled 2-1 that the specific warnings proposed by the agency violated the First Amendment.

Ruling in a separate case in March of 2012, the U.S. Court of Appeals for the Sixth Circuit upheld the law’s requirement for graphic warnings, stating that they are “reasonably related to the government’s interest in preventing consumer deception and are therefore constitutional.”

In March of 2013, the FDA stated that it planned to issue a new rule requiring graphic warnings, but the agency has not done so.

In a joint press statement, the eight health groups that brought the lawsuit charging the FDA with unlawfully delaying graphic warnings called Wednesday’s ruling a “major victory for the nation’s health and the fight against tobacco.”

“In accordance with the court’s order, we urge the FDA to quickly issue, finalize and implement a rule requiring graphic cigarette warnings,” the groups noted. “The current U.S. cigarette warnings, which are printed on the side of cigarette packs and haven’t been updated since 1984, are stale, unnoticed and a major impediment to greater progress in reducing cigarette smoking.”

At least 122 countries or jurisdictions including Australia, Canada, Mexico, and New Zealand either have graphic warning label requirements in place or have plans to implement them, according to the anti-tobacco group Campaign for Tobacco-Free Kids.

Studies suggest that warning labels on cigarette packaging are most effective at communicating health risks when they contain both pictures and words and are large and in color. They also suggest that warning labels must be rotated to avoid overexposure.

https://www.medpagetoday.com/pulmonology/smoking/74943

How tau disrupts brain-cell connections in Alzheimer’s disease

An abnormal form of the tau protein that aggregates in neurofibrillary tangles has long been implicated in Alzheimer’s disease, though the exact mechanisms behind tau’s role in the disease are unknown. Now a team of scientists led by Massachusetts General Hospital and Johns Hopkins suggest that the protein disrupts signaling within neurons to cause the disease.

By studying postmortem human Alzheimer’s brain tissue and in vitro and mouse models, the researchers found that pathological tau impairs the nuclear pore complex (NPC), a key part of the nuclear membrane that acts as the gateway for the exchange of proteins and RNA with the surrounding cytoplasm. In addition, defects in these pores might further lead to tau accumulation inside neurons. The team described their findings in the journal Neuron.

Small molecules can pass freely through the NPC, but larger molecules require assistance from interactions between transport receptors and proteins called nucleoporins, or nups, which form NPC. A signaling protein called Ran is necessary for the nuclear transport, as it regulates whether the molecule is imported or exported through the NPC.

Previous studies have linked disrupted nucleocytoplasmic transport in neurons with several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia and Huntington’s, as well as normal human aging. “In other systems, disruption of this communication causes cell misfunction and even cell death,” said co-senior author Bradley Hyman of Massachusetts General Hospital, in a statement.

Hyman and his colleagues wanted to test their hypothesis that a similar phenomenon might be happening in Alzheimer’s. They first experimented on neurons from patients with Alzheimer’s and on cellular models, and they found that Alzheimer’s-associated phosophorylated tau directly interacts with one of the most abundant nucleoporins, called Nup98. Instead of being evenly distributed in the nuclear membrane, as seen in normal control panels, the Nup98 pores were disrupted in the presence of tau, as they appeared to be depleted, and they coalesced with each other.

What’s more, the team noted that Nup98 seemed to leak into the cytoplasm, where it promoted tau aggregation. The more severe the disease was when patients were alive, the worse the Nup98 mis-location was, the team found.

They also discovered NPC leakage in mice that were genetically modified to over-express tau and develop neurofibrillary tangles. The rodents showed Ran depletion from the nucleus that appeared to correlate with the misplacement of Nups into the cytoplasm. Interestingly, after scientists suppressed the expression of abnormal tau, levels of both Ran and Nup98 in the NPC were restored.

While defective tau has long been associated with Alzheimer’s, recent research efforts have instead focused on tackling beta-amyloid, which is also widely believed to cause the condition. However, clinical studies in that field are filled with frustrations. An amyloid-fighting antibody from Biogen and Eisai recently showed cognitive benefits but still sparked debates over the significance of the data, as well as the whole amyloid theory.

The Massachusetts General Hospital and Johns Hopkins researchers suggest in their new study that preventing tau interactions with Nup98 may be promising in treating Alzheimer’s and other neurodegenerative diseases. “One of the exciting things about these findings is that, if we can block the interaction between tau and the nuclear pore, it might allow existing neurons to become more functional in patients,” Hyman said.

https://www.fiercebiotech.com/research/how-tau-disrupts-neuronal-intracellular-communication-alzheimer-s-disease

Otsuka’s dose-tracking digital pill charts its first course to market with Magellan

Get ready for the first “smart pill” to make its way to medicine cabinets. Otsuka’s Abilify MyCite, the only FDA-approved digital pill, just took another step toward patients thanks to a deal with Magellan Health to distribute the med through its network of mental health providers.

Approved to treat schizophrenia and bipolar disorder, the electronic version of Abilify is designed to help patients take their meds as directed—and, if they choose, to enlist other people in the effort.

Abilify MyCite records the date and time a patient takes a pill and relays that information, along with activity level, to a personal smartphone app where patients can add information about their mood, sleep and other health stats. If the patient allows, the dosing info also goes to their healthcare providers and caregivers.

“We are confident that being able to track drug ingestion in patients with serious mental illness will provide compelling insights for patients and their healthcare provider teams,” said Kabir Nath, president and CEO, Otsuka North America Pharmaceutical Business, in a news release.

While that may be true, the new digital pill has also faced some backlash from critics concernedabout the potential for “Big Brother”-type tracking. Some worry the technology could be used to spy on people or coerce them into drug therapy.

This first wave of use at Magellan is expected to give Otsuka and Magellan real-world data and evidence to show how well Abilify MyCite actually helps improve adherence. The collaboration also will deliver experience for physicians and patients on its day-to-day use.

While the initial rollout is purposefully small, Otsuka said it looks forward to collaborating with more payer groups going forward.

David B. Nash, chair of the Digital Medicine National Steering Board, said, in the release, “This is an exciting time, from a Population Health perspective, as we gather insights into factors that influence adherence to treatment and consider the related clinical and economic implications.”

https://www.fiercepharma.com/marketing/otsuka-digital-pill-tracker-takes-another-step-toward-reality-magellan-health-deal

Biogen enrolls patients for Phase 3 stroke trial

Biogen (Nasdaq:BIIB) announced today the enrollment of the first patient in the global Phase 3 clinical study CHARM, designed to evaluate BIIB093 (intravenous (IV) glibenclamide) for the prevention and treatment of severe cerebral edema in large hemispheric infarction (LHI), one of the most severe types of ischemic stroke where brain swelling (cerebral edema) often leads to high morbidity and mortality.

“As pioneers in neuroscience, Biogen is dedicated to advancing innovative approaches for investigational drugs in acute neurological conditions with limited or no treatments by leveraging our core expertise,” said Michael Ehlers, M.D., Ph.D., executive vice president, research and development at Biogen. “We believe IV glibenclamide could represent a first-in-class therapy with the aim of giving physicians an effective option to improve patient outcomes and reduce mortality risk. LHI is a severe type of ischemic stroke with high mortality (40 percent to 80 percent) and no currently available therapy. BIIB093 has the potential to be the first major innovation in stroke in over 20 years, and we believe the advancement to Phase 3 represents a significant milestone in our stroke clinical program.”

The CHARM study is an international, multicenter, randomized, double-blind, placebo-controlled, Phase 3 study that aims to enroll 680 patients with LHI in approximately 20 countries. It will evaluate the efficacy and safety of IV glibenclamide treatment within 10 hours following stroke onset. The primary endpoint is the modified Rankin Scale (mRS), a functional outcome, assessed at 90 days.

Each year approximately 1.7 million ischemic strokes occur in the U.S., Europe and Japan, and approximately 15 percent of these are classified as LHI. In preclinical studies, IV glibenclamide has been shown to inhibit SUR1-TRPM4 channels that mediate stroke-related brain swelling. Phase 2 proof-of-concept studies have demonstrated the potential of IV glibenclamide to reduce brain swelling associated with disability and mortality in individuals with LHI. IV glibenclamide was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the treatment of severe cerebral edema in patients with acute ischemic stroke. The FDA has also granted the CHARM study Special Protocol Assessment and IV glibenclamide Fast Track Designation.

https://www.marketscreener.com/BIOGEN-4853/news/Biogen-Enrolls-First-Patient-in-Global-Phase-3-Study-of-BIIB093-IV-Glibenclamide-for-Large-Hemis-27212724/

Novocure Treatment, Chemo Significantly Up Mesothelioma Survival

Mesothelioma patients who received Tumor Treating Fields with pemetrexed and cisplatin or carboplatin experienced median overall survival of 18.2 months compared to 12.1 months in historical control with no increase in systemic toxicity

Results support the use of Tumor Treating Fields in first potential indication outside of the brain

Company to host analyst and investor briefing Sept. 25, 2018

Novocure (NASDAQ: NVCR) announced final results from its STELLAR phase 2 registration trial in mesothelioma, demonstrating a significant extension in median overall survival among patients treated with Tumor Treating Fields plus standard of care chemotherapy compared to historical control data of patients who received standard of care chemotherapy alone. Malignant pleural mesothelioma patients who received Tumor Treating Fields with pemetrexed and cisplatin or carboplatin experienced median overall survival of 18.2 months (95 percent CI, 12.1-25.8 months) compared to 12.1 months in a historical control. Tumor Treating Fields is a cancer therapy that uses electric fields tuned to specific frequencies to disrupt cell division, inhibiting tumor growth and causing affected cancer cells to die. The final STELLAR results will be presented at the IASLC 19th World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (IASLC) on Sept. 25, 2018, in Toronto.

“The final results of the STELLAR trial demonstrate an impressive extension of median overall survival in the treatment of malignant pleural mesothelioma with no increase in systemic toxicity,” said Giovanni Luca Ceresoli, MD, Head of Pulmonary Oncology at the Humanitas Gavazzeni Hospital in Bergamo, Italy, and an investigator in the STELLAR trial. “Mesothelioma patients face an urgent unmet need for additional therapies that improve survival. Based on these data, I believe Tumor Treating Fields represent an extremely promising therapeutic option that, if approved, should be added to standard of care chemotherapy for the treatment of malignant pleural mesothelioma.”

Secondary endpoints also were improved compared to the historical control. Patients who received Tumor Treating Fields in combination with pemetrexed and cisplatin or carboplatin experienced a median progression free survival of 7.6 months (95 percent CI, 6.7-9.8 months) compared to 5.7 months in the historical control. Partial responses were seen in 40.3 percent of patients, and clinical benefit, either partial response or stable disease, was seen in 97.2 percent of patients. No serious device-related adverse events were reported. Skin irritation was reported in 46 percent of patients using Tumor Treating Fields, with only 4 patients (5 percent) reporting grade 3 skin irritation.

The single-arm, open-label, multi-center trial was designed to test the efficacy and safety of Tumor Treating Fields in combination with standard of care chemotherapy, pemetrexed combined with cisplatin or carboplatin, in 80 patients with unresectable, previously untreated malignant pleural mesothelioma. The primary endpoint was overall survival and secondary endpoints were response rate, progression free survival and adverse events. Median age of patients was 67, 84 percent were male, 56 percent were smokers, 16 percent had metastatic disease, 44 percent had an ECOG PS of 1, and 66 percent had epithelioid histology. The historical control for this trial was the 2003 pemetrexed phase 3 registration trial, which had a similar percentage of patients with epithelioid histology.

Novocure received a Humanitarian Use Device (HUD) designation for the use of Tumor Treating Fields for the treatment of malignant pleural mesothelioma in 2017 and plans to submit a Humanitarian Device Exemption (HDE) application to the U.S. Food and Drug Administration (FDA) for approval later this year.

“We are extremely pleased by the results of the STELLAR trial,” said Dr. Eilon Kirson, Novocure’s Chief Science Officer and Head of Research and Development. “We believe the results support the use of Tumor Treating Fields in our first indication outside of the brain. We are now one step closer to commercializing Tumor Treating Fields as a treatment for malignant pleural mesothelioma.”

Novocure will host an analyst and investor briefing Tuesday, Sept. 25, 2018 from 12:30 p.m. to 2 p.m. EDT in Toronto to review data presented at IASLC and to provide a general update on research and development activities. The event will be webcast live and can be accessed from the Investor Relations page of Novocure’s website, www.novocure.com/investor-relations. The webcast will be available for replay for at least 14 days following the event.

https://www.marketscreener.com/NOVOCURE-LTD-24157014/news/Novocure-Tumor-Treating-Fields-Plus-Standard-of-Care-Chemotherapy-Significantly-Extends-Median-Ove-27215378/