Antibiotics Safe for Appendicitis, 5-Year Follow-up Data Show

Antibiotics may be a feasible alternative to surgery for patients with uncomplicated acute appendicitis, 5-year follow-up data from a randomized trial show.

“Long-term follow up of patients with uncomplicated acute appendicitis suggests that initial treatment with antibiotics rather than surgery may be a feasible alternative,” write Paulina Salminen, MD, PhD, from the University of Turku, Finland, and colleagues. The researchers published the results online today in JAMA.

Although appendectomy has been the mainstay of treatment for acute appendicitis for more than 100 years, recent advances in diagnostic imaging and antibiotic therapies have allowed clinicians to consider antibiotic treatment as a viable alternative strategy in some cases.

In a recent randomized clinical trial, Salminen and colleagues found that 73% of all patients with acute uncomplicated appendicitis who received antibiotics alone did not require surgery at 1-year follow-up. However, questions remained regarding the long-term outcomes for these patients.

With this in mind, Salminen and colleagues sought to investigate the long-term recurrence rate among trial participants. The randomized Appendicitis Acuta trial was conducted at 6 hospitals in Finland and enrolled 530 adults (329 men; 201 women) with uncomplicated acute appendicitis. Of those, 273 underwent appendectomy (median age, 35 years) and 257 initially received antibiotic treatment (median age, 33 years).

With 5 years of follow-up, 3 patients had died: 2 in the appendectomy group and 1 in the antibiotics group. However, none of the deaths was considered related to the trial.

Among the 257 patients who initially received antibiotics, 100 underwent appendectomy during follow-up. Of those, 70 experienced their recurrent appendicitis within 1 year of the first episode (27.3%; 95% confidence interval [CI], 22.0% – 33.2%; 70/256), and 30 patients required an appendectomy at between 1 and 5 years (16.1%; 95% CI, 11.2% – 22.2%; 30/186).

The cumulative incidence of recurrent appendicitis among patients who initially received antibiotics alone was 34.0% (95% CI, 28.2% – 40.1%; 87/256) at 2 years, 35.2% (95% CI, 29.3% – 41.4%; 90/256) at 3 years, 37.1% (95% CI, 31.2% – 43.3%; 95/256) at 4 years, and 39.1% (95% CI, 33.1% – 45.3%; 100/256) at 5 years

“Nearly 2/3 of all patients who initially presented with uncomplicated appendicitis were successfully treated with antibiotics alone and those who ultimately developed recurrent disease did not experience any adverse outcomes related to the delay in appendectomy,” the authors write.

“These findings demonstrate the feasibility of treating appendicitis with antibiotics and without surgery,” Salminen and colleagues conclude.

In an accompanying editorial, Edward H. Livingston, MD, deputy editor at JAMA, emphasizes that one of the most important findings from this study is that patients in the antibiotics group who eventually needed surgery experienced no major complication because of delaying surgery.

“The findings from the [Appendicitis Acuta] trial dispel the notion that uncomplicated acute appendicitis is a surgical emergency,” he emphasizes. “Given that access to a surgeon is not always available, these results may have implications in many different settings and in many different countries.”

Future studies should address factors such as the optimal regimen to use for antibiotic treatment of appendicitis, says Livingston, as well as how to manage suspected recurrent appendicitis in patients who initially receive antibiotics alone.

In the AAPAC trial, patients in the antibiotics group received ertapenem (1 g/day) intravenously for 3 days while in hospital, followed by 7 days of levofloxacin (500 mg, once daily) and metronidazole (500 mg, 3 times daily). However, Livingston explains that this regimen is likely more aggressive than needed, and should be reevaluated.

The next step in appendicitis research should expand on the results from this trial to enhance nonsurgical treatment of appendicitis, he continued. “Further studies should be designed using a noninferiority approach, comparing different antibiotic approaches to that used in the [Appendicitis Acuta] study,” he concluded.

This study was supported by the Mary and Georg C. Ehrnrooth Foundation, a government research grant (EVO Foundation) awarded to Turku University Hospital, and a Turku University research grant. Salminen has reported receiving personal fees for lectures from Merck, Lilly, and Orion Pharma. The remaining authors and the editorialist have reported no financial conflicts of interest.

JAMA. Published online September 25, 2018.

https://www.medscape.com/viewarticle/902460

Insulin prices could be much lower; drug makers would still make healthy profits

As prices for diabetes treatments continue to roil consumers, a new study suggests that manufacturers could make both human and analog insulins at low costs and still pocket a profit.

After analyzing expenses for ingredients, production, and delivery, among other things, the researchers contend that the price for a year’s supply of human insulin could be $48 to $71 a person and between $78 and $133 for analog insulins, which are genetically altered forms that are known as rapid or long-acting treatments. Examples of analog insulins include Humalog, Lantus, and Novolog.

Put another way, the study estimated the cost of production for a vial of human insulin is between $2.28 and $3.42, while the production cost for a vial of most analog insulins is between $3.69 and $6.16, according to the study in BMJ Global Health.

Meanwhile, the median prices paid by more than two dozen countries for human insulin were 1.2 to 1.8 times greater than estimated prices. Median prices for other types of insulin were also higher: Lantus, which is sold by Sanofi (SNY), was 5.6 to 7.8 times higher; Humalog, which is sold by Eli Lilly (LLY), were at 2.7 to 3.7 times higher; and Novolog, a Novo Nordisk (NVO) treatment, was 2.6 to 3.5 times greater.

The study authors, who cited a 2016 study that examined government procurement prices paid and other data, argued their findings suggest greater competition would lead to sizable savings in most countries. They also maintain that existing insulin makers could set “significantly lower prices while still making a profit,” but they concede more companies would have to enter the market for this to occur.

“Anyone with Type 1 diabetes should be able to buy insulin for under $100 per year, including the long-acting forms,” said Andrew Hill, a study co-author and senior visiting research fellow at the University of Liverpool. “Pharmaceutical companies cannot justify charging governments $532 per person per year in the U.K. and $1,251 in the U.S., let alone similar amounts in low- and middle-income countries.”

There were some limitations to the study, though. For instance, biosimilar manufacturing expenses were not individually considered, such as capital expenditures, quality assurance and control, registration costs, and costs for adhering to manufacturing regulations. But the authors insisted they made a conservative assumption for the total costs of bringing a biosimilar to market.

A Sanofi spokeswoman wrote us that the drug maker “shares concerns about the affordability of medicines and is focused on ensuring people who can benefit from our medicines have access to them. As the authors noted, there were several limitations to the analysis, including a large number of assumptions which makes it challenging to draw any conclusions.”

[UPDATE: A Novo Nordisk spokesman sent us this: “We recognize that there are those who are having difficulty affording their medicine, including those made by us. We also appreciate the different perspectives across many stakeholders.  The affordability of insulin for patients depends on health systems, regardless of country. Globally, We have preferential pricing for low income countries but we’re aware that sometimes our medicines don’t reach patients because of inefficiencies and supply chains. In the U.S., we offer human insulin through several channels for approximately $25/vial.

“This study presents only one facet of the cost of medicines – the manufacturing process. It’s important to see the big picture and take a more holistic view including how the sales of the medicines fund broader R&D efforts for the next generation of medicines along with our manufacturing investments (such as our $2 billion expansion in the U.S.) when assessing cost.”]

We asked Lilly for comment and will update you accordingly.

The findings come amid ongoing controversy over the cost of diabetes treatments, which make an attractive target, given soaring prices.

A 2016 study in the Journal of the American Medical Association found the price for a milliliter of insulin climbed 197 percent from $4.34 per to $12.92 between 2002 and 2013. Two Washington lawmakers subsequently accused the three largest insulin makers — Lilly, Sanofi, and Novo Nordisk — of price collusion. The companies later publicly committed to limiting price hikes on their medicines.

Meanwhile, Nevada legislators made diabetes medicines the specific target of a transparency law that requires drug makers to report pricing histories, disclose costs, and notify state officials and insurers in advance of price hikes above inflation. The move was prompted by data showing high disease rates and the subsequent medical and economic costs to many states.

The study is likely to further embolden advocacy groups that have been trying to pressure drug makers to lower prices. In the U.S., T1 International and People of Faith for Access to Medicines are staging another demonstration this coming Sunday at Lilly headquarters in Indianapolis to protest insulin prices.

“It is unacceptable that governments and people are paying so much more than the cost of production for insulin. Estimating the cost of production for hepatitis C treatment was instrumental in getting dramatic price cuts. This needs to happen now for insulin,” said Dr. Margaret Ewen, global pricing coordinator for Health Action International, a nonprofit advocacy group that backed the study.

Indeed, the same researchers have conducted similar studies suggesting that production costs for other types of medicines were sufficiently low enough that manufacturers could slash prices and still make reasonable profits to satisfy financial goals. This work was regularly cited by patient advocates who sought to pressure drug makers to lower their prices in order to widen access to treatment, especially in low-income countries.

In reaching their conclusions, the researchers used pricing data for active pharmaceutical ingredients exported from India and price quotes from insulin makers. When API pricing could not be obtained, prices were estimated based on comparison of similarity, in terms of manufacturing process, with APIs for which prices were available. Potential biosimilar prices were estimated by adding costs of excipients, formulation, transport, development and regulatory costs, and a profit margin.

https://www.statnews.com/pharmalot/2018/09/25/insulin-prices-profits-diabetes/

Alzheimer’s biotech Alzheon sets terms for $35 million IPO

Alzheon, a Phase 3 biotech developing small molecule therapies for Alzheimer’s disease, announced terms for its IPO on Tuesday.

The Framingham, MA-based company plans to raise $35 million by offering 2.5 million shares at a price range of $13 to $15. At the midpoint of the proposed range, Alzheon would command a fully diluted market value of $196 million.

Alzheon was founded in 2013 and plans to list on the Nasdaq under the symbol ALZH. ThinkEquity and H.C. Wainwright are the joint bookrunners on the deal. IPO timing was not announced.

Relevant Profile: ALZH

https://www.renaissancecapital.com/IPO-Center/News/59978/Alzheimers-biotech-Alzheon-sets-terms-for-$35-million-IPO

FDA is considering banning online sales of e-cigarettes: Gottlieb

U.S. regulators are considering banning the online sales of e-cigarettes, the head of the Food & Drug Administration Scott Gottlieb said on Tuesday.

Gottlieb, speaking on a panel discussion on vaping that was arranged by Axios, said that the agency will release its next steps on e-cigarettes as well as data on teen vaping in November.

Earlier this month the agency said it was considering banning flavored e-cigarettes as demand from young people has increased.

https://www.reuters.com/article/us-usa-healthcare-ecigarettes/fda-is-considering-banning-online-sales-of-e-cigarettes-gottlieb-idUSKCN1M51VC

Aurinia completes enrollment of AURORA phase 3 lupus trial

Aurinia Pharmaceuticals announced that it has completed enrollment for the AURORA Phase 3 trial ahead of schedule. The target enrollment of 324 patients was surpassed due to high patient demand with 358 lupus nephritis patients randomized in sites across 27 countries. The AURORA clinical trial is a global, double-blind, placebo-controlled study to evaluate whether voclosporin when added to background therapy of mycophenolate mofetil /CellCept can increase speed of and overall renal response rates in the presence of low dose steroids. The primary endpoint for the study is complete renal response at 52 weeks, after which patients can choose to enroll into a 104-week blinded extension study.
https://thefly.com/landingPageNews.php?id=2795397

Sol-Gel expects top-line results for Epsolay in 2019

Sol-Gel Technologies announced that it has completed enrollment of half of the patients in its pivotal Phase III clinical trials of Epsolay in subjects with papulopustular rosacea, a chronic, inflammatory skin condition that most often affects the face. Epsolay is a once-daily topical cream containing encapsulated benzoyl peroxide, 5%, using Sol-Gel’s proprietary microencapsulation technology. The pivotal Phase III clinical program is being conducted in accordance with Special Protocol Assessmentagreements with the U.S. Food and Drug Administration and consists of two randomized, multi-center, double-blind, vehicle-controlled clinical trials at 50 sites in the United States. Each pivotal trial is planned to enroll 350 subjects in a 2:1 ratio of Epsolay in comparison to its vehicle, with a power of greater than 99%. The primary efficacy endpoints for both trials are success in Investigator Global Assessment, defined as a two-grade reduction in IGA on a scale of 0 to 4 with “clear” or “almost clear”at week 12, and a reduction in mean inflammatory lesion count at week 12. “The progress we have made with patient enrollment in these trials and the high interest expressed by both the patients and physicians highlights the unmet medical need for a new safe and efficacious rosacea treatment,” said Dr. Alon Seri-Levy, Chief Executive Officer of Sol-Gel. “Our goal is to advance Epsolay as a potential treatment option for papulopustular
https://thefly.com/landingPageNews.php?id=2795401

Verastem and CSPC Pharma sign license agreement to develop COPIKTRA in China

Verastem and CSPC Pharmaceutical Group announced their entry into an exclusive licensing agreement for CSPC to develop and commercialize Verastem Oncology’s COPIKTRA (duvelisib), an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, for the treatment of all oncology indications in China. COPIKTRA received approval from the U.S. Food and Drug Administration for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma after at least two prior therapies. COPIKTRA also received accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies. The indication in FL is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in trials. Under the terms of the agreement, Verastem Oncology shall receive an upfront payment of $15M. Verastem Oncology is also entitled to receive additional development milestone payments of $30M, plus potential sales milestone payments and double-digit percentage royalties based on future net sales of COPIKTRA in China. CSPC will receive exclusive rights to develop and commercialize COPIKTRA and hold the marketing authorization and product license for COPIKTRA in China. CSPC will have the right to collaborate with Verastem Oncology on certain global development and clinical trial activities and will share pro-rata in the cost.
https://thefly.com/landingPageNews.php?id=2795429