Changing Drug Landscape in Hypogonadism, Obesity, Biosimilars

Oral testosterone for adult men with androgen deficiency available, cancer concerns over lorcaserin, and push to bring more biosimilars to market.

To reduce drug costs, the FDA/FTC has put a Biosimilars plan into place to stimulate cheaper drug options.

Belviq Recalled for Concerns of Elevated Cancer Risk  

Belviq and Belviq extended release (lorcaserin) gained approved as an adjunctive therapy to lifestyle modification in patients with obesity—body mass index of at least 30 mg/k2 or of 27 mg/k2 with obesity-related comorbidities.

A post-marketing analysis of data from the CAMELLIA-TIMI-61 trial raised sufficient concern about a possible increased risk of cancer in patients taking lorcaserin for weight management that the manufacturer, Eisai, agreed to a voluntary recall.1

Originally, the CAMELLIA-TIMI-61 trial,2 was initiated to rule out concerns about potential adverse cardiovascular outcomes following use of lorcaserin over five years. While there was no evidence of an increased risk of major adverse cardiovascular events, there were findings of a reduced risk of new-onset type 2 diabetes among participants with prediabetes at baseline.

“When the FDA approved lorcaserin in 2012, we required the drug manufacturer to conduct a randomized, double-blind, placebo-controlled clinical trial to evaluate the risk of cardiovascular problems, which found that more patients taking lorcaserin (n=462; 7.7%) were diagnosed with cancer compared to those taking a placebo, which is an inactive treatment (n=423; 7.1%),”2  FDA spokesperson, Monique Richards, told EndocrineWeb.

While a range of cancer types was reported, several different types of cancers occurred more frequently in the patients receiving lorcaserin, including pancreatic, colorectal, and lung,3 said Ms. Richards, as per the Drug Safety Communication

"[O]ur review of the full clinical trial results shows that the potential risk of cancer associated with the drug outweighs the benefit of treatment,"2,3 said Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, in a drug safety communication issued by Food and Drug Administration (FDA). However, the association of increased risk of cancer and the mechanism underlying these findings remain uncertain and are pending further evaluation.

As a result, the FDA recommends that physicians discontinue further prescribing of this weight loss agent, and that patients currently taking lorcaserin be notified of the “increased occurrence of cancer seen in the clinical trial and ask them to stop taking the medicine,” Ms. Richards said.

Per the Drug Safety Communication (DSC) that was issued for Bevliq on February 13,”  the FDA is advising healthcare professionals to:3

  • Stop prescribing and dispensing lorcaserin to patients
  • Contact patients currently taking lorcaserin, inform them of the increased occurrence of cancer seen in the clinical trial, and ask them to stop taking the medicine.
  • Discuss alternative weight-loss medicines or strategies with your patients. 

“The FDA is not recommending special screening for patients who have taken lorcaserin. As with any individual patient, regardless of prior lorcaserin treatment, standard screening recommendations for cancer should be implemented,” said Ms. Richards.

Expert Clinical Comment on the FDA Request for Withdrawal of Belivq from the Market

Obesity (adiposopathy), as with every other chronic disease, requires ongoing management. From visit to visit we do explore how best to treat each chronic disease, said J Michael Gonzalez-Campoy, MD, PhD, FACE, medical director and chief operating officer of the Minnesota Center for Obesity, Metabolism and Endocrinology, Eagan, Minnesota. 

That said, "We have lots of patients taking Belviq, and we are letting [them] know it is safe and effective, they should finish what they have, and that they will have to do without it from then on. Then, as patients return to the clinic for a quarterly visit, we will address how best to help manage their weight. More likely than not patients will need to have a different medication."

"I am personally disappointed by the FDA’s request that Eisai withdraw Belviq from the US market because this decision leaves a smaller number of choices," Dr. Gonzalez-Campoy said.

In addition, he told EndocrineWeb:

  • Although the observation by the FDA holds true that the incidence of some cancers was higher on treatment than with placebo in the Camellia trial,2 it is also true that the incidence of other cancers was lower on treatment than with placebo. While withdrawing Belviq may decrease the risk of being diagnosed with some cancers, but it will also increase the risk of being diagnosed with other cancers.
  • Obesity itself is a strong risk factor for esophageal, stomach, breast, endometrial, and colon cancers, and losing a treatment option makes it more difficult to achieve success.  This equates to increased cancer risk for many patients.
  • The absolute risk  when considering over 12,000 patients, is very small no matter how you look at it, and the incidence of cancers being less than 10 cases, is much lower than the risk relative to placebo. 

"Overall, data from the Camellia trial documented that for all people treated, there was no decernable difference in cancer incidence between Belviq and placebo, he said, and there we are. 

Oral Testosterone Replacement to Treat Hypogonadism 

A prescription testosterone formulation—Jatenzo (testosterone undecanoate— is on the market for therapeutic management of a deficiency or absence of this androgen in adult men,according to the manufacturer, Clarus Therapeutics, Inc. 

This may be good news for an estimated 4 to 5 million men in the United States who have been diagnosed with hypogonadism; however, this new hormone formulation is being marketed with one caveat—it is not intended for use in age-related hypogonadism.4,5

“We are excited to announce that Jatenzo (testosterone undecanoate, [CIII]), is the first and only Food and Drug Administration-approved oral testosterone undecanoate for [hormone] replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone,” said Jay Newmark, MD, MBA, Chief Medical Officer of Clarus Therapeutics. Jatenzo is now available in the United States for appropriate men with hypogonadism.4

Specifically, Jatenzo is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired) but is not intended for use in men with hypogonadal conditions—such as “age-related hypogonadism”—that are not associated with structural or genetic etiologies.6

What changed to gain approval following the initial FDA advisory committee vote against recommending approval in January 2018?

“The 2018 conclusion of the committee, which was a very close vote, recognized the potential benefit of a safe and effective oral testosterone replacement therapy as another treatment option for men with classical hypogonadism,” Dr. Newmark told EndocrineWeb.

“There was consensus that Jatenzo would likely be safe and efficacious for appropriate men with hypogonadal men. Jatenzo was approved in March 2019. In accordance with our label, we recommend healthcare providers check patients’ baseline cardiovascular risk, ensure that blood pressure is adequately controlled, and evaluate hematocrit prior to initiating this oral therapy,” he said.

“Healthcare providers should check blood pressure and hematocrit three weeks and three months, respectively, after patients start Jatenzo or increase their dose, and clinicians should continue to check both values periodically after that,” said Dr. Newmark.

According to the company,4,5 the availability of Jatenzo offers patients an oral testosterone formulation delivered in a soft gel capsule—replacing concerns about gel transference, skin irritation from patches, or discomfort arising from injections— that other hormone delivery vehicles for testosterone relacement may produce.

Regulatory Changes Afoot to Increase Competition for More Affordable Drugs 

The Food and Drug Administration (FDA) has led a concerted effort to foster the growth of the biosimilars market begun in May of 2018, building on the Biologics Price Competition and Innovation Act based as part of the Patient Protection and Affordable Care Act.7

The goal has been to open the pathway for biological agents deemed interchangeable with and FDA-approved reference products. As such, biosimilars are viewed as an effective way to bring about significant cost savings of drugs to consumers—given that the initial list price of biosimilars has been 15% to 35% less than the reference products. 

As for the availability of any insulin biosimilar products, “currently, insulin products are regulated under the Federal Food Drug and Cosmetic Act (FD&C Act), meaning that the pathway for biosimilar competition is not yet available,” Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars in the FDA’s Center for Drug Evaluation and Research told EndocrineWeb. Similarly, there are, as yet, no biosimilars approved to treat diabetes, thyroid disease, CVD, or hormone dysfunction.

“The Biologics Price Competition and Innovation Act of 2009 (BPCI Act), requires that on March 23, 2020, an approved marketing application for a biological product under the FD&C Act be deemed to be a license for the biological product under the Public Health Service Act (PHS Act) and regulated under the PHS Act,” she said.

After this transition happens, “it will be possible for manufacturers to submit, and the FDA to approve, marketing applications for biosimilar and interchangeable biological products that reference transitioned biological products,” such as “insulin and other biological products such as human growth hormone (somatropin), pancrelipase, chorionic gonadotropin, follitropin alfa, and menotropins,” which will help ensure that the market is competitive, and patients may have more affordable access to the medications they need, said Dr. Yim.

The regulatory focus has been to streamline the approval process by stopping the practice of branded rebates and other tactics that may otherwise delay market availability. Rather, recent FDA actions have aimed to support the growth of generics and biosimilars to bring more affordable therapeutics to market, according to a statement issued by the office of the 24th FDA commissioner, Stephen M. Hahn, MD.

The Federal Trade Commission and FDA have joined forces to bring the full regulatory forces to the marketplace.7 Legislation requiring full disclosure of any biosimilar settlements to the FTC as part of its campaign to enforce healthcare-related antitrust laws in concert with FDA actions has led to the issuance of a draft guidance to address advertising and promotional labeling of biologic; the comment period remains open until April 6, 2020.


In addition, the FTC plans to use its authority to obtain and review patent settlement agreements between the manufacturers of reference products and biosimilars, and determine whether they include, among other things, anti-competitive reverse payments that curb or prevent the introduction of lower-priced drugs into the marketplace.

In furtherance of these goals, joint FDA-FTC activities aim to inhibit anti-competitive practices, such as making false or misleading statements that compare biological reference products and biosimilars, which can foster negative misconceptions about biosimilars and curtail their uptake.

To stem the practice of negative efforts directed at biologics, and specifically biosimilars, the FDA and FTC have announced a series of goals to help promote more open competition.

Taking a cue from regulatory experiences with bringing generics to the market, the biosimilar action plan was developed with four key goals:7

  • Improve the efficiency of the biosimilar and interchangeable product development and approval process;
  • Maximize scientific and regulatory clarity for the biosimilar product development community;
  • Develop effective communications to improve understanding of biosimilars among patients, health care providers and payers; and,
  • Support competition by addressing attempts to “game FDA requirements to unfairly delay market competition” of follow-on products.

According to a joint statement, the two agencies will take appropriate action, within their respective authorities, against communications that make a “false or misleading comparison between a reference product and a biosimilar in a manner that misrepresents the safety or efficacy of biosimilars, deceives consumers, or deters competition,” as well as those that could potentially impact public health. 

In addition, the FTC plans to use its authority to obtain and review patent settlement agreements between the manufacturers of reference products and biosimilars, and determine whether they include, among other things, anti-competitive reverse payments that curb or prevent the introduction of lower-priced drugs into the marketplace.

Continue Reading:
Endocrine-Related Therapeutics Garner Attention and Action at the FDA
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