#ASCO18: Loxo sees boosted response rates with LOXO-292 solid tumor med

Loxo made a big splash with its larotrectinib data at last year’s ASCO Annual Meeting, and in 2018 it’s hoping to make waves with its earlier-stage RET inhibitor LOXO-292.

Let’s rewind two weeks, when Loxo reported encouraging data from the phase 1 trial of LOXO-292 in solid tumor patients. In this test, the drug shrunk the tumors of most patients in the trial.

This was as of Jan. 5, when Loxo had treated 57 people. Almost half of the patients had RET fusion-positive non-small cell lung cancer (NSCLC). Most of the remaining participants had either RET fusion-positive papillary thyroid cancer (PTC) or RET-mutant medullary thyroid cancer (MTC). Patients with these RET alterations are poorly served by older multikinase inhibitors (MKIs).

In the abstract, released ahead of its updated ASCO data, Loxo focused on the response rate in the NSCLC and PTC patients. The overall response rate (ORR) in these RET fusion-positive patients came in at 69%. The tumors of the patients shrunk in size by as much as 67%.

Loxo also reported tumor shrinkage in the majority of MTC patients, but in most cases the change fell short of a partial response. Just two of the 14 evaluable MTC patients experienced partial responses.

The performance of LOXO-292 in the MTC cohort in fact dragged the ORR across the whole trial down to 52%. But the caveat was that Loxo was to show off data from an April cutoff, and that those were better than the data shared from the abstract.

Today, Loxo says it has those interim numbers for the “LOXO-292 global phase 1 LIBRETTO-001 dose escalation trial,” which are based on an April 2 data cutoff date.

In all, 82 patients had been enrolled to eight dose escalation cohorts, and were broken down into:

• 38 patients with RET fusion-positive non-small cell lung cancer (NSCLC) (21 with prior MKI

treatment, 17 without)

• 9 patients with RET fusion-positive thyroid cancer (8 with prior MKI treatment, 1 without)
• 2 patients with RET fusion-positive pancreatic cancer (1 with prior MKI treatment, 1 without)
• 29 patients with RET-mutated medullary thyroid cancer (MTC) (23 with prior MKI treatment, 6

without)

• 4 patients with no known activating RET alterations

In addition to a number of patients with prior MKI treatment, 46% of patients had received prior chemo, while 24% had received prior immunotherapy (47% of those with NSCLC).

The numbers are: 77% ORR for all patients enrolled with RET fusion-positive cancers, hitting the same in the RET-positive NSCLC group. In the “Other” box, which includes patients with thyroid (seven patients) and pancreatic cancers (two patients), ORR was 78%.

In RET-mutated medullary thyroid cancer (MTC), the ORR was 45%, with one complete response. Confirmed ORRs were 74% for both all RET and lung cancer patients, 71% for other, and 33% for MTC.

There were 25 partial responses in the all RET group, 20 for the NSCLC group, and five for the other and MTC group. The biotech notes that the longest responding patient on therapy was the first RET fusion-positive NSCLC patient enrolled, who had been on therapy for more than ten months as of the data cutoff date.

Loxo said its drug also “demonstrated robust reduction and clearance of RET alterations as detected in patients’ plasma cell free DNA (cfDNA).”

“The LOXO-292 Phase 1 data are striking,” said Alexander Drilon, M.D., clinical director in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and presenting author. “The activity we reported is impressive and I am thrilled to see this promising efficacy with limited adverse events, especially in this heavily pre-treated patient population of RET fusion cancers, including those with brain metastases, and RET mutated MTC.”

“We are very excited to share the initial LOXO-292 clinical experience with the oncology community at ASCO,” added Josh Bilenker, M.D., CEO at Loxo. “We have long believed that patients with RET fusion cancers and RET mutated MTC needed a purpose-built medicine tailored to their tumors. We hope that LOXO-292 continues to deliver on that premise.”

The primary endpoint of the trial assesses the maximum tolerated dose or recommended dose for further study. Secondary endpoints include safety, overall response rate and duration of response. Blueprint Medicines is also working on its experimental RET inhibitor, BLU-667, as both look to challenge existing RET products from Exelixis and Sanofi.

This comes a few days after Loxo said it was prepping for a November verdict from the FDA on its later stage effort, larotrectinib.

The Bayer-partnered drug has been awarded a priority review by the regulator for locally advanced or metastatic solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, with a target action date of Nov. 26.

https://bit.ly/2LSDKFm

Agios says Phase 1 brain cancer med data ‘encouraging’ at #ASCO18

Agios Pharmaceuticals presented the first data from the ongoing Phase 1 study evaluating single agent AG-881 in advanced glioma and other solid tumors. The data were featured in an oral presentation at the American Society of Clinical Oncology Annual Meeting. AG-881 is an investigational, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-1 and IDH2 enzymes, which was designed for enhanced brain penetrance for development in IDH-mutant glioma. “IDH mutant glioma is a distinct disease where patients are typically diagnosed in their thirties and forties and endure a deteriorating quality of life from the side effects associated with multiple rounds of surgery, radiation and chemotherapy and ultimately die of their disease,” said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center, an investigator for the study. “The AG-881 Phase 1 dose-escalation data are encouraging, as they demonstrate a favorable safety profile at lower dose levels and show signals of clinical activity that support further evaluation of the role of inhibiting mutant IDH in low-grade glioma.” “With no curative or approved targeted therapies for low-grade glioma and a poor long-term prognosis, we are committed to exploring the novel mechanism of action of our IDH inhibitors in this indication,” said Chris Bowden, M.D., chief medical officer at Agios. “Data from our ivosidenib and AG-881 Phase 1 trials and the ongoing perioperative study, combined with feedback from regulators and the neurology community, will inform our pivotal development plan.”

https://bit.ly/2J3l9IU

Texas high court rules state must reveal supplier of execution drugs

Texas must reveal the source of the drugs it uses for executions, its Supreme Court affirmed on Friday, rejecting the state’s arguments that doing so could lead to physical harm of the supplier and impede lethal injections.

Ever since a sales ban of lethal injection drugs by major pharmaceutical companies a few years ago, most states have kept the suppliers of their drugs secret. This has prompted lawsuits on behalf of death row inmates, arguing that prisoners could be subjected to unconstitutional suffering from faulty drugs in lethal injection mixes from questionable suppliers.

The Texas Supreme Court on Friday affirmed a May 2017 decision by an appellate court that said there was not enough compelling evidence provided by the state to show that there was a substantial threat of physical harm.

“Today’s decision is a win for the fundamental principles of transparency and open government,” Maurie Levin, one of the attorneys who helped bring the lawsuit on behalf of two Texas death row inmates, said in a statement.

The Texas Department of Criminal Justice said in a statement that it intends to file a motion with the court for a rehearing.

Texas has executed 551 people since capital punishment was reinstated in 1976, 37 percent of all U.S. executions and more than triple any other state, according to the Death Penalty Information Center.

Texas has also been one of the few states in the country able to procure a steady supply of execution drugs.

In 2016, pharmaceutical company Pfizer Inc (NYSE: PFE) joined a sales ban imposed years earlier by major European drug makers that did not want their products used in executions due to ethical concerns. This caused many states to scramble for suppliers and a few to suspend executions due to lack of drugs.

Although 31 states have the death penalty, only eight have held executions since Pfizer’s decision, which cut off the last major U.S. source for drugs in the lethal mixtures.

Many have turned to lightly regulated compounding pharmacies, which can mix chemicals. The states also have banned the release of the pharmacies’ names, which they have said was a security precaution.

For its lethal injection, Texas uses the barbiturate pentobarbital.

https://bit.ly/2LOlyg5

June FDA dates coming up

The month of May saw several drugs passing the FDA muster, with new molecular entity approvals alone totaling five. NMEs are those innovative new products containing active moieties that haven’t been approved by the agency previously, either as a single ingredient drug, or as part of a combination products.

Thus far this year, NME approvals have totaled 15 compared to 21 in the same period last year.

Biotech stocks had a fairly decent run thus far in May, with the iShares NASDAQ Biotechnology Index (ETF) IBB 1.28% up about 3.2 percent.

Here are some key PDUFA action dates to watch in June.

1. Valeant Psoriasis Treatment Awaits FDA Nod

• Company: Valeant Pharmaceuticals Intl Inc VRX 0.36%
• Type of Application: NDA
• Candidate: IDP-118
• Indication: Plaque psoriasis in adult patients
• Date: June 18

IDP-118 is a halobetasol propionate and tazarotene topical lotion developed by Valeant unit Ortho Dermatologics, which allows a potentially expanded duration of use. Following its first-quarter results, the company raised its revenue and EBITDA guidance for 2018.

Valeant also has two other PDUFA action dates this year, one for its NDA for altreno, an acne treatment in lotion form, scheduled for Aug. 27, and another for bryhali, a topical treatment for plaque psoriasis, scheduled for Oct. 5.

2. Will Scpharma’s Edema Treatment Pass The FDA Muster?

• Company: Scpharmaceuticals Inc SCPH 10.26%
• Type of Application: NDA
• Candidate: Furoscix
• Indication: Edema in patients with heart failure
• Date: June 23

Furoscix, if approved, will be the first formulation of furosemide, subcutaneously administered, for treating edema in patients with heart failure. The company indicated in its first-quarter earnings release that it has continued pre-launch preparations for furoscix.

3. Achaogen On Tenterhook After Mixed FDA Panel Vote On Plazomicin

• Company: Achaogen Inc AKAO 2.26%
• Type of Application: NDA
• Candidate: Plazomicin
• Indication: Complicated urinary tract infections (cUTI) and bloodstream infections (BSI)
• Date: June 25

The FDA had accepted the NDA on Jan. 2, 2018 for two indications:

• cUTI, including pyelonephritis
• bloodstream infections (BSI) due to certain Enterobacteriaceae in patients who have limited or no alternative treatment options

Achaogen suffered a setback on May 3, with shares losing one-quarter of their value, when a FDA panel issued a mixed ruling, favoring it for cUTI but nor for BSI. Since then, shares have languished around the level to which they pulled back following the Adcom meeting.

4. Will Epidiolex Give GW Pharma New Highs?

Company: GW Pharmaceuticals GWPH 0.76%

• Type of Application: NDA
• Candidate: Epidiolex
• Indication: Adjunctive treatment of seizures, with Lennox-Gastaut syndrome (LGS) and Dravet
• Date: June 27

FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, which met in April, unanimously recommended supporting the approval of epidiolex, which is purified plant-based cannabidiol oral solution (CBD) lacking the high associated with marijuana.

5. Merck’s Wonder Cancer Drug Up Before FDA For Another Indication

• Company: Merck & Co., Inc. MRK 1.73%
• Type of Application: sBLA
• Candidate: Keytruda
• Indication: Advanced cervical cancer
• Date: June 28

Merck is seeking FDA nod for its sBLA for its Keytruda- chemically pembrolizumab – for treating cervical cancer. Incidentally, this is the 14th regulatory submission for the anti PD-1 therapy.

6. Array Seeks Approval For Skin Cancer Treatment

• Company: Array Biopharma Inc ARRY 3.91%
• Type of Application: NDA
• Candidate: Binimetinib and Encorafenib
• Indication: BRAF-mutant, advanced, unresectable or metstatic melanoma
• Date: June 30

The company indicated no Adcom meeting has been scheduled.

Adcom Meeting Schedule

FDA’s Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee are set to give their decision on the NDA for remoxy, oxycodone extended-release capsules, to manage pain, severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

The NDA was submitted by DURECT Corporation DRRX 5.73% and Pain Therapeutics, Inc. PTIE 0.2%

“The committees will be asked to discuss whether the data submitted by the Applicant are sufficient to support labeling of the product with the properties expected to deter abuse,” the FDA said. Following the issue of a complete response letter on Sep. 26, 2016, the FDA accepted the refiling on March 1, 2018. The PDUFA date is set for Aug. 7.

https://bit.ly/2Jm90ym

Promise of regenerating tissues and organs from inside the body

Regenerative medicine holds tremendous promise for many ailments, from curing diabetes with pancreatic cell transplants to growing new organs for transplant. But because these approaches generate tissue ex vivo, or outside the body, scientists developing them all face the same conundrum: How can they connect these externally developed tissues to the bloodstream and the rest of the body so they can thrive?

Scientists in Wendell Lim’s lab at UC San Francisco hope that a synthetic signaling molecule, dubbed synNotch, will allow scientists to create tissues and organs within the body, with ready-made connections. They used synNotch to program groups of cells to differentiate into different types of structures, mimicking how cells naturally “talk” to each other and decide how to organize themselves into tissues, according to a statement. Specifically, they programmed cells to respond to signals coming from adjacent cells by making “sticky” molecules called cadherins and fluorescent marker proteins.

They made a series of increasingly more complicated structures, starting with a two-layered sphere. A group of colorless cells expressing synNotch were programmed to detect a signal protein expressed by a second group of blue cells. When combined, the blue cells activated the clear cells’ synNotch, prompting them to produce the velcro-like cadherins and a green marker protein. This caused the colorless cells to clump together and turn green, forming the core of the sphere, surrounded by an outer layer of blue cells.

While the structures the team built were relatively simple, “these minimal intercellular programs were sufficient to yield assemblies with hallmarks of natural developmental systems: robust self-organization into multidomain structures, well-choreographed sequential assembly, cell type divergence, symmetry breaking and the capacity for regeneration upon injury,” they wrote in their study, which appears in Science. Lim thinks that combining multiple layers of synNotch signaling will pave the way for the generation of “ever more complex” tissues.

“People talk about 3D-printing organs, but that is really quite different from how biology builds tissues. Imagine if you had to build a human by meticulously placing every cell just where it needs to be and gluing it in place,” said Lim, a Howard Hughes Medical Institute investigator and member of the UCSF Helen Diller Family Comprehensive Cancer Center, in the statement. “It’s equally hard to imagine how you would print a complete organ, then make sure it was hooked up properly to the bloodstream and the rest of the body. The beauty of self-organizing systems is that they are autonomous and compactly encoded. You put in one or a few cells, and they grow and organize, taking care of the microscopic details themselves.”

In a similar tack, researchers in the U.S. and Japan developed a new cell culture method to combat a problem with pancreatic islets—the tendency to lose their blood vessels when they are being prepared for transplant. The method, called self-condensation cell culture, allowed the scientists to grow new pancreatic islets complete with endothelial cells, which improved post-transplant engraftment.

SynNotch was first developed in Lim’s lab by co-authors Kole Roybal and Leonardo Morsut. At the time, they used it to tweak T cells, improving their ability to recognize cancer cells and destroy them. The technology has the potential to make engineered T-cell treatments more specific and therefore applicable in solid tumors. It could also be used to suppress the immune response, which could be useful in treating autoimmune disease, the scientists said at the time.

https://bit.ly/2LS0Dcf

GSK collaborates on AI-driven drug design with Cloud Pharmaceuticals

GlaxoSmithKline (GSK) is set to apply artificial intelligence (AI) technology to improve its drug discovery efforts through a collaboration with Cloud Pharmaceuticals.

Its deal with the US-based AI-driven drug design and development company will see Cloud design novel small-molecule agents to GSK-specified targets.

Ed Addison, CEO of Cloud Pharmaceuticals, said: “Application of Cloud Pharmaceuticals technology has been proven to dramatically shorten the time from target validation to lead molecule.

“We believe this agreement validates the strength of this process and reinforces the value we can offer accelerate the discovery of novel, high-quality drug candidates.”

Set up in 2009, Cloud aims to use its technology to accelerate the drug discovery and design process by using a proprietary AI-driven process to deliver novel molecules tailored to a drug target’s characteristics.

Don Van Dyke, COO of Cloud, said: “It is estimated that the traditional discovery process to arrive at a clinical candidate molecule takes greater than five years. Cloud has consistently been able to reduce that to a matter of a few months.”

The collaboration marks Cloud’s first big pharma deal, but for GSK it adds to the $33 million deal it signed with Scotland’s ExScientia last year to apply that firm’s AI technology to speed up its drug discovery efforts.

It is, however, GSK’s first major AI move since appointing Karenann Terrell last July to the newly-created post of chief digital and technology officer.

Commenting then on Terrell’s appointment GSK chief executive Emma Walmsley said Terrell would be given the scope to “think radically about how we can exploit the latest opportunities and ultimately improve our business performance”.

But GSK isn’t the only company looking to buck the continuing downward trend in conventional pharma R&D productivity by harnessing new technology.

Two of the sector’s latest deals have seen Pfizer partner with US-based AI firm XtalPi to develop molecular modelling software for drug-like small molecules and Mitsubishi Tanabe Pharma tie up with Hitachi to apply AI to improve the efficacy of its drug development efforts.

https://bit.ly/2srv6FL

FDA approves UCB’s Cimzia in plaque psoriasis

The US FDA has approved a label extension for UCB’s Cimzia (certolizumab pegol) for adults with moderate-to-severe plaque psoriasis, marking the company’s entry into immuno-dermatology, an area with significant unmet need.

Cimzia is indicated for the treatment of adults with moderate-to-severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy. The approval makes Cimzia the first Fc-free, PEGylated anti-TNF treatment option for this indication.

Lead investigator Alice Gottlieb, Professor of Dermatology at New York Medical College, said that the phase 3 clinical development programme for Cimzia in plaque psoriasis demonstrated statistically significant improvements in efficacy endpoints at week 16, with a clinically meaningful response maintained up to week 48.

“This compelling body of evidence is especially significant for a disease like psoriasis, which often has significant emotional and social burdens in addition to the more widely-recognised physical symptoms,” she explained. “The two dose regimens of Cimzia also allow for patient-tailored treatment.”

Emmanuel Caeymaex, head of Immunology and executive vice president, Immunology Patient Value Unit, at UCB, said, “The approval of Cimzia for psoriasis and the recent Cimzia label update regarding pregnancy and breastfeeding in women with chronic inflammatory diseases are important treatment advances. UCB is committed to improving care for psoriasis patients and is also investigating bimekizumab, a therapy with significant potential for psoriasis patients.”

This FDA approval is based on data from a phase 3 clinical development programme, comprising CIMPASI-1, CIMPASI-2 and CIMPACT. The trials enrolled over 1,000 patients, nearly one third of whom had prior biologic exposure.

Each of the three studies included an assessment of the percentage of patients who achieved at least 75% and 90% or greater disease improvement from baseline, as measured by the Psoriasis Area and Severity Index (PASI 75 and PASI 90, respectively) compared to placebo.

The positive findings from the trials, and the new approval in psoriasis that they support, are significant because they build on four years of efficacy and safety data in psoriatic arthritis (PsA).

The recommended dose of Cimzia for adults with moderate-to-severe plaque psoriasis is 400 mg (given as two subcutaneous injections of 200 mg each) every other week. For some patients (with body weight ≤ 90 kg), Cimzia 400 mg (given as two subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every other week can be considered.

“Due to the unique nature of psoriasis, it is critical for dermatologists to have as many options as possible to find the right treatment for each patient,” said Michael Siegel, PhD, senior vice president of Research and Clinical Affairs, National Psoriasis Foundation.

Psoriasis is a common, chronic inflammatory disease primarily affecting the skin. Signs and symptoms vary but may include red patches of skin covered with silvery scales, dry, cracked skin that may bleed and thickened, pitted or ridged nails.

Psoriasis affects nearly 3% of the population, or approximately 125 million people worldwide. Those with more severely affected, psoriasis can have a major impact on their quality of life. As many as 42% of patients develop psoriatic arthritis, 33% develop metabolic syndrome, and approximately 46% are depressed because of their psoriasis.

https://bit.ly/2szhgAn