Leg Amputations Declined Among End Stage Renal Disease Patients

The rate of lower extremity amputations dropped by more than half in patients with end-stage renal disease (ESRD) on dialysis during a recent 15-year period, according to an analysis of a large U.S. database.

In 2000, the adjusted rate of lower extremity amputations in this patient population was 5.42 per 100 person-years (95% CI 5.28-5.56). In 2014, that rate dropped to 2.66 per 100 person-years (95% CI 2.59-2.72), for a decrease of 51%, said Tara Chang, MD, of Stanford University in Palo Alto, Calif., and colleagues.

The rate of above-knee amputations decreased by 65%, compared with 58.5% for below-knee amputations and just 26% for below-ankle amputations, Chang’s group reported online in JAMA Internal Medicine.

One-year mortality rates after lower extremity amputation also decreased in ESRD patients on dialysis but remained high. In 2000, the rate was 52.2%, and that fell to 43.6% in 2014, the study found.

“This decrease in the amputation rate among patients with ESRD contrasts with the 69% increase in the amputation rate observed from 1991 to 1994 and mirrors the decreasing trend in amputations, which was also driven by a decrease in major amputations reported for the general Medicare population from 1996 to 2011,” Chang’s group wrote.

“The reasons for the declining amputation rate cannot be directly gleaned from our observational analysis. We postulate that one factor may be more aggressive cardiovascular risk factor management, given the declining prevalence of coronary artery disease and of recognized PAD [peripheral arterial disease] observed during the study period.” In addition, improvements in foot care among patients with diabetes could be another potential factor, the researchers said, citing a study that found monthly foot checks were associated with a 17% decrease in amputation rates.

“Although the large decrease in rates of lower extremity amputation among patients with ESRD is encouraging, absolute amputation rates remained high when compared with reported rates in the general Medicare population.” For example, in 2011, the rate was more than 20-fold higher among patients with ESRD compared with the general non-ESRD Medicare population (2.88 versus 0.12 per 100 person-years), the study found.

Study Details

Chang et al analyzed data from the U.S. Renal Data System on all Medicare patients initiating dialysis from 2000 to 2015 — more than three million patients in all. Their mean age was 63; more than half were white (58% in 2000 and 57% in 2014), and less than half were women (48% in 2000 and 44% in 2014). The primary outcome was the number of lower extremity amputations per 100 person years for each year, identified using the International Classification of Diseases, Ninth Edition (ICD-9) procedure codes and Current Procedural Terminology, 4th Revision (CPT-4) codes. The secondary outcome was 1-year mortality rates post amputation.

The investigators calculated amputation rates for each year, using the first year, 2000, as a reference and adjusting for multiple factors including age, race, ethnicity, employment status, Medicaid dual eligibility, cause of ESRD, dialysis modality, dialysis vintage, cardiovascular disease, cerebrovascular disease, PAD, hypertension, diabetes, and smoking.

Amputation rates among ESRD patients with diabetes also decreased by more than half, but remained more than five times higher than for those without diabetes during the study period. For example, in 2014, the rate among patients with diabetes was 4.09 per 100 person years (95% CI 3.99-4.19) compared with 0.74 (95% CI 0.69-0.79) for those without diabetes.

Rates were also higher among men than women. In 2014, the rate for men was 3.01 per 100 person years (95% CI 2.92-3.10) compared with 2.21 (95% CI 2.13-2.30) for women. “These results are consistent with previous studies showing that diabetes and male sex are significant risk factors for amputation in the non-ESRD population,” Chang’s group said.

An analysis by hospital referral regions found that amputation rates tended to be higher in the South and Northeast regions of the United States compared with the West and Midwest. “The persistent regional variation could stem from differences not captured in our analysis, such as in intensity of vascular care, differences in surgical practice patterns, uncaptured socioeconomic variables, or structural differences in the healthcare system management of PAD or diabetes.”

The study was limited to patients who had Medicare parts A and B as the primary payer, and the results might not be generalizable to patients with private insurance, the authors noted. Nevertheless, they said, the analysis highlights the need for more research on ways to prevent lower extremity amputations in this high-risk population.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Stanford Cardiovascular Institute.

Chang reported financial relationships with Janssen, Novo Nordisk, and Fresenius Medical Care; other co-authors also reported relationships with pharmaceutical companies.

• Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 07.09.2018

• Primary Source

  JAMA Internal Medicine

  Source Reference: Franz D, et al “Trends in rates of lower extremity amputation among patients with end-stage renal disease who receive dialysis” JAMA Internal Medicine 2018; DOI: 10.1001/jamainternmed.2018.2436

https://bit.ly/2N0S52f

Germs grow on medical implants; can they make you sick?

Bacteria and fungi grow on medical implants, such as hip and knee replacements, pacemakers and screws used to fix broken bones, researchers report.

In a new study, Danish investigators examined 106 implants of different types and the surrounding tissue in patients. The findings showed that 70 percent of the implants had been colonized by bacteria, fungi or both.

However, none of the patients with bacteria or fungi on implants showed signs of infection, according to the team at the University of Copenhagen, Denmark.

“This opens up a brand new field and understanding of the interplay between the body and bacteria and microbiomes,” said study co-author Thomas Bjarnsholt, a professor in the university’s immunology and microbiology department.

“We have always believed implants to be completely sterile. It is easy to imagine, though, that when you insert a foreign body into the body, you create a new niche, a new habitat for bacteria,” he explained in a university news release.

“Now the question is whether this is beneficial, like the rest of our microbiome, whether they are precursors to infection or whether it is insignificant,” Bjarnsholt said.

None of the discovered bacteria or fungi were dangerous, the researchers said.

According to study co-author Tim Holm Jakobsen, “It is important to stress that we have found no direct pathogens, which normally cause infection. Of course if they had been present, we would also have found an infection.” Jakobsen is an assistant professor of immunology and microbiology.

“The study shows a prevalence of bacteria in places where we do not expect to find any. And they manage to remain there for a very long time probably without affecting the patient negatively,” he added.

“In general, you can say that when something is implanted in the body it simply increases the likelihood of bacteria development and the creation of a new environment,” Jakobsen said.

The study was published online July 2 in the journal APMIS.

More information

The U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases has more on joint replacements.

https://bit.ly/2L1o3ec

MabVax Secures $11M from Boehringer Ingelheim for Antibody Development

Shares of MabVax Therapeutics have more than doubled this morning after Boehringer Ingelheim inked a deal to acquire the rights to an antibody development program that will be used to target multiple solid tumors.

Under terms of the deal, Boehringer Ingelheim will pay MabVax $11 million in upfront money for the preclinical product. The preclinical asset sold to Germany-based Boehringer Ingelheim targets a glycan commonly overexpressed on multiple solid tumor cancers, MabVax said in its announcement. Additional funds could head to the San Diego-based company from downstream milestone payments. The news was pleasing to investors who snapped up shares of MabVax this morning. The stock has jumped more than 300 percent from Friday’s close of 59 cents per share to a morning high of $2.46 per share.

The stock though is shooting up ahead of MabVax’s delisting from the Nasdaq exchange. The company announced on July 2 that it would not attempt to regain compliance with the Nasdaq to remain on the exchange. Trading of the company’s common stock will be suspended at the open of business on Wednesday, July 11. Nasdaq will thereafter take action to formally remove the Company’s securities from listing and registration on Nasdaq, the company said Thursday.

David Hansen, president and chief executive officer of MabVax, said the asset BI acquired is based on the company’s proprietary HuMab technology.

“This agreement with Boehringer Ingelheim recognizes the value of our innovative approach to discovering novel antibodies to diagnose and treat cancer. We have been committed since the founding of the company to discovering and developing unique fully human antibodies to diagnose and treat patients with cancers where there remain significant unmet medical needs.
Hansen said in a statement.

MabVax said the preclinical antibody series that is part of the deal with Boehringer Ingelheim was discovered from biological samples, originally from patients who were vaccinated against their solid tumors with a glycan antigen-containing vaccine. The discovery of fully human antibodies directly from vaccinated cancer patients has potential advantages which include greater specificity and reduced toxicities, the company said. Following the discovery, MabVax said it reported on early preclinical development activities to establish the utility of the program.

MabVax said the deal with Boehringer Ingelheim does not involve its lead HuMab-5B1antibody program, which is in Phase I clinical trials. MabVax’s Phase I antibody, MVT-5873, is a fully human IgG1 monoclonal antibody (mAb) that targets sialyl Lewis A (sLea), an epitope on CA19-9. MVT-5873 is being studied as a potential therapy for pancreatic cancer, as well as other cancers that have CA19-9 positive tumors. CA19-9 plays an important role in tumor adhesion and metastasis, and is a marker of an aggressive cancer phenotype. In April 2017, the company announced preclinical results for MVT-1075 at the American Association of Clinical Research (AACR) annual meeting. The results showed the drug demonstrated marked suppression and regression of tumor growth in xenograft animal models of pancreatic cancer.

https://bit.ly/2KS42dp

Investment Bankers Leave Firms for Roles in Hong Kong Biotech Companies

More and more pharma companies follow the trend of planning initial public offerings on the Hong Kong Stock Exchange. Another trend following this path is the number of prominent investment bankers who have left their firms for biotech companies in the former British colony.

Since December, Bloomberg reported that at least seven “senior bankers and analysts from top-tier securities firms” have left their lofty positions in the financial sector to take roles in biotech companies based in Hong Kong. The shift is a response to a recent rule change regarding the listing of IPOs on the Hong Kong Stock Exchange. The rule change allows companies to IPO even if they are not yet profitable. Several U.S. companies are rumored to be preparing to take advantage of that change. Among those companies are GRAIL, Inc., which secured a whopping $300 million in an oversubscribed Series C financing round led by multiple Chinese investment groups earlier this summer. Other companies that have planned IPOs this year in Hong Kong include Ascletis, which planned on raising $100 million in a Series C round earlier this year. In May Ascletis filed for an IPO on the Hong Kong exchange as it prepares to launch its hepatitis C treatment Danoprevir by September.

The investment bankers and analysts moving into the biotech world are leaving noted companies like Goldman Sachs, Bank of America Corp., Deutsche Bank AG, Citigroup Inc. and Jefferies Group LLC, Bloomberg reported. The latest banker to leave his post is Richard Yeh, a healthcare analyst with Goldman Sachs. He is taking over the role of chief financial officer at CStone Pharmaceuticals, a Chinese immuno-oncology company.

JHL Biotech, which de-listed from the Taiwan Stock Exchange earlier this year, hired two of the seven bankers to bolster its leadership team ahead of a potential Hong Kong IPO, Bloomberg said. Ellis Chu and Lee Henely, both formerly with Bank of America, took positions with JHL in May. JHL plans on seeking a $35 million IPO next year, Bloomberg said.

In an interview with Bloomberg, Chu said he is “getting in on a sector” where he sees “huge potential.”

“Biotech is an industry that’s exploding, yet still in its infancy in China. There are all sorts of tailwinds,” Chu said.

BioSpace has reported on the significant expansion of the biotech industry in China – an expansion that is expected to continue for years to come. IQVIA (formerly QuintilesIMS) data shows China’s pharmaceutical market is expected to grow to between $145 billion and $175 billion by 2022. Last year Lan Huang, the chief executive officer of BeyondSpring, told BioSpacethat China is a well-spring of biotech opportunity. Huang predicted that companies will increasingly make use of China’s clinical resources to lower time and cost in drug development.

https://bit.ly/2KUOhlT

Gilead’s senior clinical research director joins Nimbus to help lead drug discovery

Gilead Sciences’ senior director of clinical research, Adrian Ray, has moved over to Nimbus Therapeutics to become its senior vice president of discovery biology.

After 15 years at Gilead, Ray will help advance Nimbus’ programs aimed at underlying targets that link oncology, immunology and metabolic disease. The Cambridge, Massachusetts-based in silico drug discoverer has been focusing on tyrosine kinase 2 and the stimulation of interferon genes, or STING, including under an immunology collaboration with Celgene.

“Adrian is a capable leader in target discovery throughout the metabolic-oncology-immunology target space, and in the translation of these discoveries into effective clinical development strategies. We’re thrilled to have him,” Nimbus CEO Don Nicholson said in a statement.

Nimbus and Gilead have worked closely before, culminating in the Big Pharma’s 2016 acquisition of Nimbus’ acetyl-CoA carboxylase inhibitor program—a $1.2 billion deal that included a $400 million upfront payment, plus R&D milestone dollars—which Gilead is currently developing in nonalcoholic steatohepatitis.

Late last year, Gilead said higher doses of its NASH drug, GS-0976—which Nimbus moved from initial screening to phase 1 in 16 months—had seen statistically significant reductions in liver fat after three months in a phase 2 study. That news followed positive proof-of-concept data from April 2017, as well as a $200 million research milestone payout.

Meanwhile, Nimbus recently raised $65 million in a new financing round in June, including funds from Microsoft founder Bill Gates, who provided part of Nimbus’ 2011 seed funding, plus money from Atlas Venture, SR One, Lilly Ventures, Pfizer Venture Investments, Lightstone Ventures and Schrödinger.

Nimbus’ preclinical Tyk2 program signals pro-inflammatory cytokine receptors that provide targets in several auto-immune disorders including lupus, Crohn’s disease, psoriasis, multiple sclerosis, rheumatoid arthritis and others. Separately, STING agonists play a role in antitumor immunity, while STING antagonists may also have therapeutic potential in diseases such as lupus where it fuels an interferon response.

The company also boasts several partnerships, including with Genentech, Charles River Laboratories and Proteros, as well as Massachusetts General Hospital and the Salk Institute for Biological Studies.

https://bit.ly/2KM5OO5

Cytori has data on erectile dysfunction cell therapy

A one-off injection of stem cells into the penis has restored erectile function in some men undergoing prostate removal surgery—even if they didn’t respond to conventional ED drugs like Viagra.

Erectile dysfunction (ED) is a common side effect of a radical prostatectomy and, while some patients can be treated, a sizable proportion get no benefit from conventional drug therapies. There have been a lot of anecdotal reports that stem cell therapy can be a benefit, but clinical evidence is lacking.

Cytori and investigators in Denmark have tried to provide clinical support for the idea via an open-label phase 1 trial of adipose-derived regenerative cells (ADRC) in 21 patients, including 15 who were urinary-continent after surgery and six who were incontinent.

The results were pretty positive, overall, and shares in the company were up nearly 12% premarket even though the therapy missed one endpoint in the trial, which was published in the journal Urology.

Based on one efficacy scale—the International Index of Erectile Function-5 (IIEF-5)—Cytori’s therapy achieved a significant improvement in sexual function overall, but was unable to hit that target on the accompanying erection hardness score (EHS) measure. However, there may be an explanation for the result, which comes down to how badly the men were affected after the surgery.

A subset of 15 patients who didn’t develop urinary incontinence after the prostatectomy did even better on the IIEF-5 measure, and also saw a statistically significant benefit on EHS. And among that continent group, more than half (53%) recovered enough erectile function to have intercourse during the course of the 12-month study.

The results throw a lifeline to men who can’t resolve ED problems with oral drugs like Pfizer’s Viagra and Eli Lilly’s Cialis, which are both PDE5 inhibitors, or direct injections with prostaglandin-based drugs into the penis. Where these fail, the last resort for patients is typically a penile implant.

Drug treatments for ED represent are a massive market estimated at around $4.5 billion in 2016, although generic competition is eating into branded product sales, so a one-off stem cell therapy offers an intriguing opportunity.

It’s worth noting, however, that private clinics around the world have been offering stem cell treatments for ED “without preceding rigorous clinical data regarding safety and efficacy,” according to the Danish team led by Martha Haahr Ph.D., of Odense University Hospital.

The new 12-month data reinforce six-month results in 17 subjects reported in 2016, but the authors said their study is limited by being unblinded, which means they can’t rule out a placebo effect or indeed the possibility that the improvements would have happened spontaneously over time.

“The next step before stem cell therapy can be made available to patients is to perform a randomized blinded and placebo-controlled trial among continent men,” they wrote in the paper.

It’s a positive trial for Cytori nevertheless, and comes as the biotech is carrying out another trial to see if ADRC therapy can tackle stress urinary incontinence after radical prostatectomy, another common side effect of this type of surgery. Data from this study, called ADRESU, are due in the first half of 2019.

https://bit.ly/2zpGAQe

China speeds cancer drug price cuts amid outcry over smuggled Indian generics

Get ready, cancer drugmakers. China is eyeing speedier price cuts on oncology drugs, thanks to an outcry over a movie that publicized smugglers sneaking cheaper generics into the country. And the drugs targeted for cuts are mostly Big Pharma therapies.

The country’s newly formed, all-powerful health insurance administration aims to deepen discounts on cancer drugs already on its National Reimbursement Drug List (NRDL). The effort would use public bidding and procurement specifically centered on cancer therapies. Meanwhile, officials will start enlistment negotiations for treatments not yet included on the coverage list, according to the state-run China Central Television.

A new focus on cancer costs was announced during a government press conference in late April, right before the country removed import tariffs and reduced import value-added tax to 3% on all cancer therapies. The government hopes drugmakers will factor in those favorable tax moves when pitching prices on their therapies.

Last year, China forced two rounds of NRDL negotiations after seven years of stasis. More than a dozen cancer drugs, including AstraZeneca’s Iressa and Roche’s Herceptin, are now covered by the country’s insurance program, but only after the companies agreed to huge discounts—a typical move trading lower prices for higher volume. Demand for Herceptin, for example, surged after the discount, triggered a national shortage.

Now, because of the Chinese regulator’s streamlined drug review process, new and more effective cancer treatments like AstraZeneca’s Tagrisso and Bristol-Myers Squibb’s Opdivo are entering the market at unprecedented speed. That, in turn, has pushed the government to negotiate prices more often and make therapies accessible to patients more quickly.

Beijing’s recent declaration came as a dark comedy movie—”Dying to Survive”—that touched off nationwide debate on cancer drugs’ high prices. The film is based on the true story of Lu Yong, a leukemia patient who smuggles a cheap Indian-made Gleevec copycat not approved in China. The film raked in $200 million in four days at the Chinese box office, and sparked a public outcry, not to mention demands for lower prices on life-saving cancer drugs.

But getting drug prices as low as possible, or following India’s looser generics policies, isn’t the way forward for China, at least according to one researcher.

In an interview with China’s business news outlet Jiemian, Zhu Hengpeng, a Chinese healthcare reform expert who heads the Center for Public Policy Research at the Chinese Academy of Social Sciences, warned that pushing drug prices too low could hurt innovation in the long run, for domestic drugmakers in particular. He argued that global firms—usually first to market—have the financial power to cope with lower prices in China, thanks to revenues they collect in Western countries before their products go off patent. However, burgeoning domestic firms must rely on a relatively higher price to make up for R&D costs, he said.

Public bidding that pits manufacturers of the same type of drug against each other might not be the biggest threat for multinational drug developers, at least for now, because many treatments still lack competition in China. But local firms are catching up, and the Chinese government has already put through policies that support generics. For instance, the country has adopted generic names, instead of brand names, in all healthcare settings, and launched tax incentives for high-quality generics makers.

What’s more, in an effort to contain insurance spending, China is piloting reimbursements based on indications instead of services. Under that program, hospitals would be given a fixed payment for each patient treated for a particular disease. With their own finances at stake, doctors would have less incentive to use high-cost drugs.

https://bit.ly/2Nx13Wh