Tuesday, February 5, 2019
Notable Labs Teams with NonProfit in Pediatric Cancer Partnership
One argument for the high price of some prescription drugs put forth by biopharma companies is due to the significant investments made in taking an asset from a concept, through multiple clinical trials and the regulatory process, all before making it available for sale.
One company though may have found an alternative to offset drug development costs as it moves forward with plans to develop a treatment for a rare form of leukemia and then distribute the drug at a low cost. As Foster City, Calif.-based Notable Labs prepares to initiate clinical testing on its compound ND1000, the company has partnered with the non-profit organization Cures Within Reach to provide a path to distribute the drug to patients. Notable will donate the commercial rights to price, manufacture, and distribute ND-1000 for pediatric leukemia to Cures Within Reach. The nonprofit will then provide the drug to pediatric leukemia patients at a very low cost. Cures Within Reach has a mission to, in part, support the repurposing of a drug for patients.
“The idea of the partnership with Cures Within Reach was born from a conversation on how to do something different to bring a therapy to market that’s affordable for all patients,” Notable Labs Founder Matt De Silva told BioSpace in an exclusive interview.
Through the partnership, Cures Within Reach will be able to use its status as a nonprofit organization to raise funds to help financially support Notable’s clinical development of ND1000. Once the drug makes its way through the clinic, and then potentially through regulatory approval, Notable will then be able to see potential payment because the drug will be eligible for the U.S. Food and Drug Administration’s Pediatric Priority Review Voucher Program. The voucher has a significant financial value and can be sold to other companies, De Silva said.
“The vouchers are really valuable and can be sold to other companies,” De Silva said. He noted that the vouchers can fetch between $60 million and $300 million, which would be suitable compensation for Notable and its other development projects. In total, the company has 15 drugs in development, with ND100 the first into the clinic. De Silva said another blood cancer drug, one for myeloid leukemia, is expected to go into the clinic later this year.
Notable’s ND1000 is a combination drug. It’s a blend of a generic drug already used in cancer patients, one not disclosed, and a natural product that has been used as a treatment for cancer. The natural product was also not disclosed. But, combined, ND-1000 is expected to enhance immunotherapy treatments already in use for these patients, such as CAR-T therapies. It does so by upregulating three proteins CD-19,-20 and -22. Most of the patients who will benefit from ND1000 have already failed multiple treatment options, so the patient pool is fairly small, only a few hundred in the U.S., De Silva said.
Under the partnership with Cures Within Reach, Notable will keep the proceeds from the FDA voucher and the nonprofit will have the drug for as close to cost as possible, De Silva said. This type of partnership that the two companies have developed is a first-time approach, De Silva said.
Notable Labs, now has 35 employees, was founded by De Silva, a former analyst at noted biotech investor Peter Thiel’s Clarium Capital, nearly five years ago. De Silva said the concept for the company came out of his experiences caring for his father, who was diagnosed with glioblastoma multiforme. None of the approved medications benefitted the elder De Silva and he was not eligible to participate in any clinical trial due to the advanced form of the disease. De Silva said that all of the treatment solutions for his father were sort of a “one-size-fits-all” approach. De Silva wanted to find a way to focus on personalized treatment for individual cancer patients, and Notable Labs was born. The company is currently focused on blood cancers, but De Silva said he still thinks about going after the cancer that killed his father.
“This is just the beginning of our story,” he said.
Pain Therapeutics Criticizes FDA After Meeting Over Thrice-Rejected Remoxy
Investors are not happy after Austin, Texas-based Pain Therapeutics announced that it was no closer to seeing its drug candidate Remoxy ER, an abuse-deterrent, extended-release gel formulation of oxycodone, approved by the U.S. Food and Drug Administration (FDA).
The FDA issued a Complete Response Letter in August for the company’s opioid-treatment, Remoxy. The CRL was issued after an advisory committee voted overwhelmingly against approval of Remoxy in June of 2018. In November, Pain Therapeutics announced it planned to meet with the FDA to go over its concerns with the CRL.
As a result of the meeting the company had with regulators on Jan. 31, the company said it is “no closer today to product approval than we were over a year ago.” The company requested the meeting in order to resolve a disagreement around comments and conclusions made by FDA in 2018 during a regulatory review of the New Drug Application for Remoxy. During the meeting, Pain Therapeutics said it learned that the FDA denies that any mathematical errors, material mistakes or misrepresentations were made during a June 2018 advisory committee meeting, despite what the company said was “clear evidence to the contrary.” Pain Therapeutics added that it was told it would need to rely on the Freedom of Information Act to access additional data generated by FDA with Remoxy.
Remi Barbier, president and chief executive officer of Pain Therapeutics, said Remoxy is “an odyssey without a homecoming.” He criticized the FDA’s handling of the meeting. Barbier said the company hoped for a “fair, neutral and impartial review” of the data for Remoxy. However, Barbier claimed he and other company executives “walked out of this meeting feeling a bit disoriented by FDA’s lack of transparency, clarity or helpfulness.” He noted that it was rare when two parties cannot agree on math.
“We can’t work with shambolic regulations. This is not how you win support for innovation,” Barbier said in a statement.
As result, share prices have fallen 10 percent during Tuesday’s trading to $1.08 as of 2:05 p.m.
Barbier noted that the company has spent more than $100 million to develop Remoxy. Over the course of the development, there have been some stumbles. Not only with the most recent FDA rejection, but also a previous rejection from the FDA in 2008. After a series of deals surrounding Remoxy, the drug was resubmitted to the FDA in 2010 and was again rejected. The second time, pharma giant Pfizer was attached to the drug through a licensing deal. Pfizer said it intended to address the issues outlined in the CRL, but then opted to abandon it and give the rights back to Pain Therapeutics, BioSpace reported earlier. Two years ago the FDA kicked Remoxy back to Pain Therapeutics over concerns of potential abuse. That led to the latest request for regulatory approval, which was again rejected by the FDA.
Barbier said this morning that the analgesic efficacy of the drug is not in question, but there is a difference of opinion around the drug’s abuse-deterrent properties. Barbier said the clinical data supports the company’s view of abuse-deterrence, while the FDA argued against the point.
“We are unable to follow the logic by which a drug product should never release the drug. More generally, as the regulatory requirements for Remoxy have changed frequently and suddenly over time, we have experienced significant delays and have incurred unanticipated expenses related to the overall Remoxy development program,” Barbier said.
As the company moves forward, Barbier said Pain Therapeutics will “generally be silent” regarding its plans for Remoxy, “unless a significant material event occurs that compels us to update our public disclosures around this product candidate.” In December, the company moved forward with a Phase II program that could be a potential first-line treatment in patients with Alzheimer’s disease. The mid-stage asset, PTI-125, targets an altered form of Filamin A, which some studies show is responsible for multiple pathologies observed in the Alzheimer’s brain.
Intercept, Gilead, Pfizer And Genfit In NASH: Overview Of Q1 2019 Catalysts
Liver Therapy Forum weekly digest provides an overview on what’s happening in the NASH ecosystem in Q1/2019.
Due to the significant interest in liver therapeutics-focused investment opportunities, I highlight anticipated catalytic events that could increase or decrease stock value in Q1/2019.
Currently, over 30 drug candidates are in different phases of clinical trials for NASH.
This weekly newsletter provides news-related events with a focus on FDA, clinical trials and financials on stocks focused on the development of liver therapeutics.
Clinical Trials
NASH is a progressive chronic liver disease with many causal pathogenic factors. We have learnt from research that dysregulation of the glucose and lipid metabolic pathways could be associated with the development of NASH. Inflammation and activation of the apoptotic (i.e. cell death) machinery have both been reported to promote the development of NASH. NASH is often labeled a ‘silent disease’ because it is asymptomatic. Internally, the effects of NASH in the body is not a silent effect, with its pathogenic effects in the liver now being increasingly recognized: steatosis (i.e. fatty liver), inflammation, fibrosis and cirrhosis, all characteristic of NASH.
Regardless of the causal pathogenic factor(s), NASH is a 2-phase disease, early and late phase, with great unmet needs. In the absence of FDA-approved therapeutics, the prevalence of NAFLD, the precursor for NASH, and NASH are both expected to increase dramatically in the USA and globally in 2019 and beyond. Unfortunately, beginning 2020, NASH is expected to surpass HCV infection as the main cause of liver transplant. With over 30 drug candidates in clinical development for early phase or late phase NASH, a lot catalytic events are expected in Q1/2019 and beyond.
Top Line Data Readout
In Q1/2019, top line data readouts are expected from two Phase 3 anti-NASH drug candidates, selonsertib by Gilead (NASDAQ:GILD) and obeticholic acid by Intercept (NASDAQ:ICPT). Regardless of your investment preference, clinical history would be made in the NASH world. I also know some of you may agree with me that these are major catalytic events that could be a HUGE upside or downside for both companies. I have updated my thesis on these drug candidates in the liver therapy forum and would not discuss clinical expectations in this digest.
Weight loss surgery changes the way our bodies sense food
How bariatric surgery helps people with obesity and diabetes is related to changes in the way the gut senses food and nutrients after the operation, researchers report February 5 in the journal Cell Reports. They found that following surgery, altered patterns of digestion and absorption lower in the gut trigger production of higher levels of gut hormones, especially glucagon-like peptide 1 (GLP-1), which in turn causes higher insulin production.
“For people who have gastric bypass surgery to treat obesity and who also have diabetes, after surgery body weight is reduced and the diabetes melts away quickly,” says senior author Fiona Gribble of the Cambridge University Metabolic Research Laboratories at the Wellcome Trust — MRC Institute of Metabolic Science. “But in lean patients with gastric cancer, they start off having normal glucose control and after the operation they end up having frequent hypoglycemic episodes because their sugar levels dip.” The team wanted to learn more about the mechanism explaining these opposite results regarding glucose management.
Researchers have long known that bariatric surgery changes how the food you eat is digested and absorbed down the gut. They also knew that hormone-producing cells in the gut, such as GLP-1 and peptide-YY (PYY) are elevated afterwards. But they did not know the precise connection between these facts. For this study, the team decided to focus on GLP-1 as it is a major hormone involved in diabetes treatment. At least a half dozen GLP-1-based medications are available for managing Type 2 diabetes. “Our theory was that the high GLP-1 levels produced after surgery are quite important for improving your blood glucose after surgery,” says Gribble.
The team studied five individuals receiving bariatric surgery for a hereditary form of gastric cancer. Participants received Exendin-9, a compound that blocks the action of GLP-1, at the same time as taking glucose by mouth. They found that concentrations of insulin, the hormone responsible for lowering blood glucose levels, did not increase as dramatically when these individuals were given Exendin-9 and did not suffer hypoglycemic episodes. “We found that blocking the GLP-1 hormone with the Exendin-9 blocked its effect on the pancreatic beta cells that produce the insulin,” says Gribble.
The team also wanted to know why GLP-1 levels rise so high after surgery. Normally, food is digested and absorbed high up in the gut. But after surgery, it happens lower down because of the gut rearrangement that involves a Y-shape connection between the bile and pancreatic enzymes with the food. “Most digestion does not happen until the bile and the pancreatic enzymes coming down from one side join the food coming down the other side, which occurs lower in the gut,” explains Gribble. That is important because most GLP-1 is released lower down the gut. “If you digest and absorb your nutrients a bit lower down, you consequently stimulate the release of much more GLP-1.”
Using new RNA sequencing and mass spectrometry-based measurements they developed for this research, the team mapped the location of various hormonal peptides in the gut in humans and mice before and after surgery. They found that the cells producing the GLP-1 hormone and other gut hormones are not affected by the surgery. “This means that the reason for higher GLP-1 secretion is not because the surgery changes the hormone production by the gut, but it is because nutrient digestion and absorption happens in a different place in the gut and that causes higher levels of GLP-1 and PYY,” says Gribble.
Looking forward, the team hopes to learn the precise mechanism responsible for the rapid weight loss in bariatric surgery. “If you can work that out and make a therapy that mimics that, that is what everyone wants: an injectable or oral medication that could mimic the surgery and cause weight loss in people without the surgery,” she says. And for those suffering from hypoglycemia after gastric cancer surgery, development of a compound that blocks GLP-1 on a more permanent basis may help improve quality of life for patients who currently make significant adaptations to their eating behavior to avoid hypoglycemic episodes.
Story Source:
Materials provided by Cell Press. Note: Content may be edited for style and length.
Journal Reference:
- Pierre Larraufie, Geoffrey P. Roberts, Anne K. McGavigan, Richard G. Kay, Joyce Li, Andrew Leiter, Audrey Melvin, Emma K. Biggs, Peter Ravn, Kathleen Davy, David C. Hornigold, Giles S.H. Yeo, Richard H. Hardwick, Frank Reimann, Fiona M. Gribble. Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery. Cell Reports, 2019; 26 (6): 1399 DOI: 10.1016/j.celrep.2019.01.047
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