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Sunday, June 2, 2019

Follow-up studies often lacking for cancer drugs approved early

  • Cancer drugs are often approved quickly by the Food and Drug Administration. In many cases, however, initial evidence of efficacy is never confirmed by studies testing for a survival benefit, according to new research published Tuesday in JAMA Internal Medicine.
  • Just a fifth of cancer drug approvals between 1992 and early 2017 were eventually supported by clinical trials demonstrating an improvement in patient survival, researchers found. More than 40% of the time, the follow-up trials used to confirm early results tested the same surrogate measure, such as progression-free survival.
  • Surging industry investment in oncology, coupled with the FDA’s desire to speed patient access to new cancer drugs, has resulted in a steady stream of approvals from the agency. Many of those drugs come with annual price tags stretching to six figures, making what patients are getting for the cost a critical question.

Cancer drugmakers are frequently the beneficiary of accelerated approvals from the FDA. Over the past four years, 17 of the 22 treatments granted an early, conditional OK by the agency were cancer treatments.
And under recently departed agency chief Scott Gottlieb, the FDA intensified its efforts to speed new therapies to market.
Gottlieb has defended the agency’s evolving approach to evaluating new cancer drugs, citing advances made in targeted therapy and in selecting the right patients for clinical study.
“We’re trying to balance competing needs,” he said in a speech last June. “The need for high degrees of statistical certainty, and the need for access to care.”
Soon after Gottlieb’s speech, the FDA published a list of surrogate endpoints used by the agency to approve cancer drugs, hoping be more transparent in how it decides to clear drugs without evidence of a survival benefit.
Two studies published this week in JAMA Internal Medicine, however, call into question that approach and argue for stricter management of how drugs are OK’d on an accelerated basis.
One, from researchers at Brigham and Women’s Hospital, Harvard Medical School and Queen’s University in Canada, details how few drugs approved on an accelerated basis ever end up being supported with survival data.
The study authors examined 93 cancer drug approvals for 64 separate products which were conditionally granted by the FDA between 1992 and May 31, 2017. Clearance was given based on surrogate measures like progression-free survival and overall response rate, which some have arguedare poorly correlated with clinical outcomes.
Just 19 of those approvals were eventually backed up by confirmatory studies showing an improvement in overall survival. Researchers found many of the studies used by drugmakers to confirm initial findings used surrogate endpoints as well — and, also in 19 cases, the same surrogate.
Notably, in only five cases was a conditional approval withdrawn as a result of negative confirmatory data.
The other JAMA study, conducted by researchers at Oregon Health and Science University, found that for 85 cancer drug indications the median response rate used to support approval was 41%. Fourteen of those approvals were granted based on data showing tumor response rates less than 20%.
Taken together, the two study findings “raise several doubts about the success of the accelerated approval process,” wrote Sarah DiMagno and colleagues from the University of Pennsylvania in commentary also published Tuesday.
They argue that the FDA should not permit drugmakers to use the same surrogate endpoint in confirmatory study, and call for more rapid withdrawal of approval if follow-up results show significant toxicity or no clinical improvement.
“The reliance on surrogate end points has real costs for patients and society,” they wrote. “Drugs with unproven effectiveness sell false hope to desperate patients, who are likely paying thousands of dollars out of pocket for them.”
Researchers in both studies did acknowledge, however, the wide range of differences in cancer types, differences that can change the context for use of a surrogate measure or for interpreting response rates.

Chronic disease biotech Morphic Holding files for an $86 million IPO

Morphic Holding, which is developing oral small-molecule integrin therapeutics for various chronic diseases, filed on Thursday with the SEC to raise up to $86 million in an initial public offering.
The Waltham, MA-based company was founded in 2014 and booked $9 million in collaboration revenue for the 12 months ended March 31, 2019. It plans to list on the Nasdaq under the symbol MORF. Morphic Holding filed confidentially on April 12, 2019. Jefferies, Cowen, BMO Capital Markets and Wells Fargo Securities are the joint bookrunners on the deal. No pricing terms were disclosed.

Schizophrenia biotech Karuna Therapeutics files for a $75 million IPO

Karuna Therapeutics, a Phase 2 biotech developing therapies for schizophrenia and other CNS disorders, filed on Friday with the SEC to raise up to $75 million in an initial public offering.
The Boston, MA-based company was founded in 2009 and plans to list on the Nasdaq under the symbol KRTX. Karuna Therapeutics filed confidentially on March 29, 2019. Goldman Sachs, Citi and Wells Fargo Securities are the joint bookrunners on the deal. No pricing terms were disclosed.

Illinois To Become 11th State To Legalize Recreational Marijuana

Illinois lawmakers approved the legalization of non-medical marijuana and sent the measure Friday to Gov. J.B. Pritzker who is expected to sign it, making the state the 11th in the country to allow recreational cannabis use.

What To Know

The legislation would allow residents 21 and older to legally be in possession of 30 grams of cannabis, 5 grams of cannabis concentrate or 500 milligrams of THC in a cannabis-infused product. Nonresidents could possess 15 grams of cannabis. Pritzker, who became governor in January, included legalization of marijuana in his platform when campaigning last year.
Pritzker also was pushing for the measure for financial reasons. He had banked on licensing and tax revenue to balance the state’s budget.
The House passed the bill Friday after the Senate approved it on Thursday.
Illinois would become the first state to legalize adult-use, or recreational, cannabis use through a proposal initiated in the legislature, rather than being required to do so by a voter initiative.

Why It’s Important

The measure also calls for expungement of the records of people with prior convictions for possession of less than 30 grams of cannabis. It also calls for taxation of cannabis sales based on concentration.
It also decriminalizes home growing of small amounts of cannabis – replacing jail time with a fine – and allows home cultivation of small amounts for medical marijuana patients.
“This is a great day for the people of Illinois who soon will be able to exercise their right to wellness through access to safe and regulated cannabis,” Ben Kovler, CEO of Green Thumb Industries Inc GTBIF 6.05% told Benzinga. “The benefits of adult-use legalization are many: much-needed tax revenue, regulation to ensure safe products, criminal justice reforms to counteract the failed war on drugs, and an alternative to opioids and alcohol.”

Biotech Week Ahead, June 3

Biotech stocks came under pressure this week ahead of the ASCO 2019 presentations. Headlines on legal woes related to the opioid crisis and drug price manipulation led to weakness in some stocks.
The unfolding week is all about the presentations at one of the largest educational and scientific events for the oncology community.
Here are the key events/catalysts to look forward to:

Conferences

  • The American Society of Clinical Oncology, or ASCO, 2019 Annual Meeting – May 31–June 4, in Chicago, Illinois
  • The European Academy of Allergy and Clinical Immunology 2019 Annual Congress – June 1-5, in Lisbon, Portugal
  • 20th Global Nephrologists Annual Meeting – June 3-4, in London
  • Jefferies 2019 Healthcare Conference – June 4-7, in New York City
  • European Society for Pediatric Gastroenterology, Hepatology and Nutrition 2019 Annual Meeting – June 5-8, in Glasgow, Scotland
  • HBV Cure Meeting – June 7-8, in Singapore
  • The American Diabetes Association’s 79th Scientific Sessions – June 7-11, in San Francisco, California

PDUFA Dates

The FDA is scheduled to rule Monday on Merck & Co., Inc. MRK 0.61%‘s sNDA for Zerbaxa (ceftolozone and tazobactam) in treating adult patients with ventilated nosocomial (hospital-acquired) pneumonia

ASCO Presentations On Sunday, June 2

  • Aduro BioTech Inc ADRO 4.84% – Phase 1b data for ADU-S100 and Spartalozumab (solid tumors or lymphomas)
  • Celgene Corporation CELG 0.82% – Phase 1/2 data on CC-220 (relapsed and/or refractory multiple myeloma)
  • CAN-FITE BIOPHA/S ADR CANF 1.33% – already-released Phase 2 data for Namodenoson (second-line treatment of advanced liver cancer)
  • Amgen, Inc. AMGN 1.38% – Phase 1 data for AMG 420 (relapsed, refractory multiple myeloma)
  • ZIOPHARM Oncology Inc. ZIOP 3.6% – Phase 1 data for Ad-RTS-Hil-12 (recurrent glioblastoma) as well as initial Phase 1 data for Ad-RTS-Hil-12 plus veledimex in combination with Bristol-Myers Squibb Co BMY 1.16%‘s Opdivo (refractory glioblastoma multiforme)
  • VBI Vaccines Inc VBIV 4.04% – Phase 1/2a expanded Part A data for VBI-1901 in recurrent glioblastoma multiforme
  • Puma Biotechnology Inc PBYI 2.19% – additional Phase 2 data for Neratinib monotherapy with high dose loperamide prophylaxis (extended adjuvant treatment of early-stage HER-2 positive breast cancer)
  • AstraZeneca plc AZN 0.36% and Merck – already-released Phase 3 data for Lynparza (pancreatic cancer)

ASCO Presentations On Monday, June 3

  • Blueprint Medicines Corp BPMC 2.93% – updated Phase 1 data for BLU-667 (RET-altered solid tumors)
  • Actinium Pharmaceuticals Inc ATNM 10.3% – Phase 3 data for Iomab-B (hematopoietic stem cell transplantation)
  • Amgen – Phase 1 data for AMG510 (solid tumors)
  • Agios Pharmaceuticals Inc AGIO 2.66% – updated Phase 1 data for Ivosidenib (IDH1 mutant newly diagnosed AML ineligible for standard therapoes) as well as updated Phase 1 data for Ivosidenib in combination with Vidaza for newly diagnosed AML with an IDH1 mutation) and Phase 1 data for Ivosidenib and Vorasidenib (IDHm low-grade glioma)
  • Incyte Corporation INCY 0.17% and Novartis AG NVS 0.22% – already-released Phase 2 data for INC280 (non-small cell lung cancer)
  • Forty Seven Inc FTSV 9.94% – Phase 1b data for 5F9 in AML as well as Phase 1b data for 5F9 + Azacitidine in AML
  • Incyte – Poster presentation of Phase 2 data for INCB54828 (cholangiocarcinoma)
  • Corcept Therapeutics Incorporated CORT 2.2% – Phase 1/2 data for relacorilant plus Arbaxane (solid tumors)
  • Seattle Genetics, Inc. SGEN 3.95% – full Phase 2 data for enfortumab vedotin (urothelial cancer)
  • MEI Pharma Inc MEIP 3.05% – Phase 1b data for ME-401 (relapsed/refractory follicular lymphoma/chronic lymphocytic leukemia)
  • Constellation Pharmaceuticals Inc CNST 1.41% – interim Phase 2 data for CPI-060 and ruxolitinib (myelofibrosis)
  • Stemline Therapeutics Inc STML 1.65% – Phase 2 data for SL-401 (chronic myelomonocytic leukemia)
  • Nektar Therapeutics NKTR 2.46% – Phase 2 data for NKTR-214 and Opdivo (sarcomas)
  • Stemline Therapeutics & Epizyme Inc EPZM 1.58% – updated Phase 2 data for Tazemetostat (epithelial sarcoma)

ASCO Presentations On Tuesday, June 4

  • Roche Holdings AG Basel ADR RHHBY 0.51% – Phase 3 overall survival data for Tecentriq plus nab-paclitaxel (triple-negative breast cancer)
  • MacroGenics Inc MGNX 4.68% – detailed Phase 3 data for Margetuximab (metastatic breast cancer)
  • Roche & AbbVie Inc ABBV 1.15% – Phase 3 data for Venclexta plus Gazyva (chronic lympocytic leukemia)
  • Celgene – updated Phase 1 data for Liso-cel (chronic lymphocytic leukemia)
  • Puma Biotech – already-released Phase 3 data for Neratinib (third-line HER2-positive metastatic breast cancer)
  • Atara Biotherapeutics Inc ATRA 2.68% – Phase 1 data for autologous T cells (malignant pleural disease)
  • TG Therapeutics Inc TGTX 3.09% – Phase 2/3 MZL cohort data for TG-1101 and TGR-1202 (non-Hodgkin lymphoma)

Other Presentations

AnaptysBio Inc ANAB 2.69% is due to present on Wednesday Phase 2a data for ANB020 in severe adult eosinophilic asthma at the European Society for Pediatric Gastroenterology, Hepatology and Nutrition 2019 annual meeting.
Spring Bank Pharmaceuticals Inc SBPH 4.79% will present full data for Inarigivir 400mg in healthy volunteers at the HBV Cure Meeting
Opko Health Inc. OPK 2.7% is scheduled to present already-released Phase 2b topline data for OPK88003 in obesity and diabetes at the American Diabetes Association’s 79th Scientific Sessions.
Albireo Pharma Inc ALBO 0.09% is set to present on June 7 Phase 2 data for Odevixibat in biliary atresia at the European Society for Pediatric Gastroenterology, Hepatology and Nutrition 2019 annual meeting

IPO Quiet Period Expiry

Axcella Health Inc AXLA 0.14%
Cortexyme Inc CRTX 2.1%
NextCure Inc NXTC 2.87%
Milestone Pharmaceuticals Inc MIST 2.32%
Applied Therapeutics Inc APLT 0.5%

CVS Health Mounts Defense of Aetna Deal on Two Fronts

CVS Health Corp. will defend its acquisition of insurer Aetna Inc. in two high-profile settings Tuesday, seeking to sell skeptical investors and a federal judge on the nearly $70 billion deal.
CVS lawyers will be in a Washington, D.C., federal court for the start of an unusual three-day proceeding in which U.S. District Judge Richard Leon is considering whether the Justice Department adequately protected competition when it approved the deal last year.
In New York, the Woonsocket, R.I.-based health-care company will hold an investor day to discuss its outlook, with analysts looking for evidence that CVS can improve its financial performance amid challenges to its core businesses.
The deal, reached in November, combined CVS’s sprawling network of pharmacies and pharmacy-benefit-management business with Aetna’s health-plan assets. Coming together, the companies had sketched a vision of lowered health-care costs and improved care for consumers.
A CVS spokesman declined to comment on the investor day or the court hearing.
The Justice Department’s antitrust division approved the merger after the companies agreed to sell off Aetna’s Medicare Part D drug business to WellCare Health Plans Inc. The department said the divestiture was needed because Aetna and CVS had been important competitors in selling Medicare drug plans to seniors in 22 states.
Groups like the American Medical Association said the divestiture didn’t do enough to protect competition for prescription-drug plans, and they argued the department didn’t address broader concerns about health-care industry consolidation.
The criticism caught the attention of Judge Leon, who is considering whether to approve the settlement between the companies and the Justice Department. Judges typically give the nod to such settlements as a matter of routine — and without extended consideration — but Judge Leon made clear he has concerns about the deal, and he took the unprecedented move of scheduling three days of hearings with live witness testimony.
The judge insists that the proceedings aren’t a mini-trial of a merger that the government isn’t seeking to block, saying the testimony would help him determine whether the settlement is in the public interest.
Judge Leon, a George W. Bush appointee, said he would hear from six witnesses: three critical of the merger and three selected by CVS to testify in favor of the deal, including executives from CVS and Aetna.
For its part, the Justice Department said in a May 24 filing that Judge Leon’s rules for the proceedings were unfair because the company could neither present its own witnesses nor cross-examine those critical of the settlement. Judge Leon said his procedures were appropriate, rejecting what he described as the department’s “11th-hour request” to change them.
It isn’t clear what would happen next should the judge reject the Justice Department settlement allowing the merger. Meantime, CVS is moving forward as if the court proceedings won’t impact its business. The company already has sold the assets to WellCare that the Justice Department required, and it has contractual obligations to provide support to WellCare through 2019, regardless of whether the court formally approves the agreement.
CVS faces challenges that have affected its rivals as well, including a squeeze on pharmacy margins and government scrutiny of the traditional pharmacy-benefits business model, particularly rebates paid by drugmakers. Health insurers’ shares have also been dragged down by some Democrats’ support for universal government health coverage. There were “pressures on all the legacy businesses that accelerated heading into this year,” said Matthew Borsch, an analyst with BMO Capital Markets.
In February, CVS gave a downbeat earnings projection for 2019, pushing its shares down sharply and leading investors to press for more detail about the company’s growth plans. The shares have remained stagnant, despite stronger-than-expected first-quarter results, and CVS has promised a fuller picture of its future in the Tuesday session.
A JPMorgan Chase & Co. poll of investors found their highest priorities for the CVS investor day were long-term financial guidance and a clear strategic vision. Among respondents who didn’t own CVS shares, a third said the session might convince them to buy. “Their credibility can be restored based on their ability to lay out the strategy and numbers,” said Lisa Gill, a JPMorgan analyst.
Analysts polled by Refinitiv were projecting earnings per share of $5.02 in 2019, $5.66 in 2020 and $6.67 in 2021. On an adjusted basis, they predicted earnings per share of $6.85 for 2019, a 5.4% increase to $7.22 for next year and growth of 8% to $7.80 for 2021.
“It’s really about operating earnings and their ability to grow that,” said Kevin Caliendo, an analyst with UBS.
Investors are also looking for specifics around CVS’s plans to build up its health-care role in the wake of the merger, say analysts, including through new health hub stores designed to offer a broader range of services, many aimed at those with chronic illnesses. Problem areas such as the company’s troubled Omnicare long-term-care pharmacy business are also likely to draw questions, they said.

Alzheimer’s-Cholesterol Connection

Elevated low density lipoprotein (LDL) cholesterol levels were tied to a higher probability of early-onset Alzheimer’s disease, a case series showed.
Early-onset Alzheimer’s patients had higher LDL cholesterol, total cholesterol, and apolipoprotein B (Apo B) levels, even after adjusting for the apolipoprotein E ε4 (APOE E4) allele — a genetic risk factor known to raise circulating cholesterol — reported Thomas Wingo, MD, of Emory University in Atlanta, and colleagues.
Moreover, early-onset Alzheimer’s cases were strongly associated with rare variants of APOB, which codes for the major protein of LDL cholesterol, they wrote in JAMA Neurology.
“A big question is whether there is a causal link between cholesterol levels in the blood and Alzheimer’s risk,” Wingo told MedPage Today. “The existing data is murky on this point.”
“Our current work is focused on testing whether there is a causal link,” he continued. “If there is a causal link between Alzheimer’s disease and cholesterol, we might need to revise targets for LDL cholesterol to help reduce Alzheimer’s risk.”
Early-onset Alzheimer’s occurs before age 65 and has a large genetic basis with heritability of 91% to 100%. Mutations in three genes that cause Alzheimer’s — amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) — were discovered in families with early-onset disease, but most likely account for less than 10% of incident cases.
In this analysis, Wingo and colleagues studied three potential causes of early-onset Alzheimer’s: Alzheimer’s genetic variants, circulating plasma lipoproteins, and APOB, which is known to harbor rare variants with strong effects on raising or lowering LDL cholesterol.
To collect this data, they sequenced APOBAPPPSEN1, and PSEN2 in samples from 2,125 early-onset cases and controls recruited from 29 Alzheimer’s disease research centers from 1984 through 2015. They also measured plasma cholesterol levels in 267 frozen samples collected from early-onset Alzheimer’s patients and controls from 2009 to 2014 at Emory University and the University of California San Francisco Alzheimer’s research centers.
Of the 2,125 samples that underwent genetic sequencing, 1,276 were from women (60.0%) and 654 (30.8%) were from patients with early-onset Alzheimer’s. The average age of early-onset patients was 55.6 and the average age of controls was 72.
In this group, only 3.4% carried APPPSEN1, and PSEN2. The APOE E4 allele — the largest known genetic risk factor for late-onset Alzheimer’s — accounted for 10.1% of the variance. “These results collectively confirm that these four genes account for only a minority of the strong genetic predisposition seen in early onset Alzheimer’s disease, and additional genes are likely to be involved,” noted Makoto Ishii, MD, PhD, of Weill Cornell Medicine in New York City, in an accompanying editorial.
After controlling for APOE E4, early-onset cases had higher levels of total cholesterol (mean difference 21.9 mg/dL, P=2.9 × 10-5), LDL cholesterol (mean difference 22.0 mg/dL, P=1.8 × 10-6), and Apo B (mean difference 12.0 mg/dL, P=2.0 × 10-6) than controls in the 267 plasma samples. Adjusting for age showed similar results.
Deep resequencing showed that rare APOB coding variants were significantly more abundant in early-onset Alzheimer’s cases, after taking sex, APOE E4, genetic principal components, and study center into account (effect size 0.20; P = 4.20 × 10-4).
“Overall, this is an important study that provides the first evidence that rare genetic coding variants of APOB are strongly associated with early-onset Alzheimer’s disease,” Ishii observed. Consistent with these findings, a transgenic mouse model overexpressing APOB had significant memory impairment and increased beta-amyloid levels compared with wild-type mice, he noted.
“However, previous studies measuring circulating apolipoprotein B levels in humans have been inconclusive, with a large population study finding no association between circulating apolipoprotein B levels and incident dementia or Alzheimer’s disease,” he continued. “Therefore, whether these findings can be verified in individuals with late-onset Alzheimer’s disease remains to be determined.”
The study suggests other contributing factors — possibly rare variants in other genes involved directly in LDL cholesterol metabolism — may be involved, Ishii added. And while this analysis focused on cholesterol, “similar studies investigating other cerebrovascular risk factors, such as insulin resistance or type 2 diabetes mellitus in individuals with early-onset Alzheimer’s disease, may be equally enlightening,” he wrote.
The findings generate a number of questions, including whether APOB has protective and deleterious variants and what role APOB variants may play in late-onset Alzheimer’s disease, noted Wingo and colleagues.
The analysis also has several limitations, they noted. It does not infer causality and because of the rarities of the alleles tested, could not be analyzed using Mendelian randomization. Cholesterol data may be confounded by Alzheimer’s severity, smoking, or cholesterol-lowering drugs, but the genetic link between APOB and early-onset Alzheimer’s is unlikely to be affected by these variables, they added.
The study was supported by the Veterans Health Administration, the NIH, the Emory Integrated Genomics Core, the To Remember Foundation, the Douglas French Alzheimer’s Foundation, and the State of California Department of Health Services, Alzheimer’s Disease Research Center of California.
Researchers disclosed relevant relationships with the NIH, the NIA, the VA, Avid Radiopharmaceuticals, Eli Lilly, Piramal Imaging, GE Healthcare, Eisai, Axon Neuroscience, Merck, Genentech, Roche, Quest Diagnostics’ Dementia Pathway Collaboration, Cornell University, the Bluefield Project, Avanir Pharmaceuticals, AbbVie, Novartis, Biogen, Cognito Therapeutics, Future Health, and Takeda.
Editorialist Ishii was supported by the NIH and owns stock in Regeneron Pharmaceuticals.

Comments
NIR TSABAR
June 1, 2019
Parallel lines don’t meet.. Only randomized controlled trials (RCTs) can tell us whether any i n t e r v e n t i o n to lower cholesterol will benefit humans in fighting Alzheimer’s disease. Since LDL is a known physiologic vehicle of our organism to deliver metabolites needed for cell functions, and since our normal brains contain lots of lipids and cholesterol, and since statin RCTs repeatedly failed in preventing dementia, and since loss of memory or depression are side effects of statins – this line of intervention will probably won’t work.
Gary DeBacher
June 2, 2019
It is time to stop looking for causes and to start treating. There has long been evidence that low-dose lithium prevents ADL, and can reverse it in its early stages. Cannabidiol promises to replace lithium as a method to clear amyloid and tau from the hippocampus, and to provide strong general neuroprotection.
I agree entirely with the previous commenter.