Qilu Pharmaceutical Secures First-to-File Approval for HIV Combination Therapy; Novo Nordisk's Once-Weekly Insulin Rejected by FDA; Bayer Restructures China Operations

A total of 3 briefs | Reading time approximately 3 minutes◆◆ ◆

01

Qilu Pharmaceutical's First Generic AIDS Drug Approved

On July 16, Qilu Pharmaceutical's Entecavir and Rilpivirine Hydrochloride and Tenofovir Alafenamide Fumarate Triple Combination Tablets for the treatment of HIV-1 infection received marketing approval from the National Medical Products Administration. This product is the first generic drug combining Entecavir, Rilpivirine Hydrochloride, and Tenofovir Alafenamide Fumarate to be approved for marketing in China.

The original research drug of Entecavir and Rilpivirine Tablets is Odefsey from Gilead Sciences. Odefsey is a three-in-one combination agent (R/F/TAF), containing 200 mg of emtricitabine, 25 mg of rilpivirine, and 25 mg of tenofovir alafenamide fumarate (TAF). It was first approved for marketing in the United States in March 2016 for the treatment of HIV infection, and subsequently approved in Europe and Japan. It has not yet been marketed in China. According to the PharmaCube database, the global sales of Odefsey in 2023 were $1.35 billion.

Entecavir, Rilpivirine, and Tenofovir Alafenamide Tablets consist of entecavir, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Entecavir is a nucleoside reverse transcriptase inhibitor that blocks the synthesis of viral DNA chains. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor that inhibits viral replication by non-competitively inhibiting HIV-1 reverse transcriptase and exhibits broad-spectrum antiviral activity against various HIV-1 subtypes. Tenofovir alafenamide is converted into its active form, tenofovir, in the body, and then undergoes phosphorylation to become tenofovir diphosphate, which induces termination of viral DNA chain replication. The combination regimen of these three drugs has proven efficacy and is recommended by guidelines as an antiviral treatment for both adult and adolescent patients who are new to therapy. The single-tablet formulation is more convenient to take, requiring only one tablet per day, which helps reduce the medication burden on patients and improve adherence.

(Source: PharmaCube Info)

02

Novo Nordisk Insulin Rejected by FDA

Novo Nordisk's insulin products have been constantly in the spotlight recently.

First, in March last year, the three insulin giants—Lilly, Sanofi, and Novo Nordisk—successively announced decisions to cut prices for their insulin products and pledged to adhere to the U.S. federal government’s proposed $35 price cap strategy. Later, Novo Nordisk also decided to withdraw its basal insulin Levemir from the U.S. market, drawing significant attention in both the pharmaceutical industry and political circles. More recently, at an FDA advisory committee meeting, the Endocrinologic and Metabolic Drugs Advisory Committee voted against approving Novo Nordisk's once-weekly insulin icodec. The FDA advisory committee initially voted 7 to 4 that the benefits of insulin icodec did not outweigh its risks. Experts pointed out that, compared to Novo Nordisk's daily injection formulation Tresiba (insulin degludec), the once-weekly icodec carried a higher risk of hypoglycemia. Subsequently, the FDA officially rejected icodec.

Once-weekly icodec

Icodec is a once-weekly basal insulin analog that meets the weekly basal insulin needs through once-weekly subcutaneous injection. Its Phase III study, ONWARDS, targets both Type 1 and Type 2 diabetes. The biggest potential advantage of icodec lies in the injection frequency, with patients only needing 52 injections of icodec per year compared to possibly 365 injections for regular basal insulin. Icodec is also being developed to address the issue of many Type 2 diabetes patients delaying insulin therapy.

Studies have found that 50% of type 2 diabetes patients who require insulin treatment delay the start of insulin therapy for various reasons, with an average delay of up to 15 months. One-third of insulin users do not adhere to the once-daily insulin injection regimen. Fifty percent of doctors believe that the frequency of injections contributes to compliance issues among patients using daily injectable insulin. A once-weekly injectable formulation could help address the issue of basal insulin injection frequency.

Icodec extends the half-life to approximately 7 days by modifying the human insulin molecule. Specifically, icodec introduces three amino acid substitutions in the insulin molecule, significantly enhancing its molecular stability, minimizing enzymatic degradation of icodec, and reducing receptor-mediated clearance.

Compared with once-daily insulin, icodec insulin achieves similar glucose-lowering effects at steady state (after three to four injections) with significantly fewer injections.

Icodec Causes Hypoglycemia Adverse Reaction

To support its approval application for type 1 diabetes, Novo Nordisk provided data from the Onwards 6 trial, which showed that icodec can achieve glucose control no less effective than daily basal insulin. However, according to its briefing document, the investigational once-weekly regimen resulted in a higher risk of "clinically significant" or "severe" hypoglycemic episodes.

In Onwards 6, compared with insulin degludec, the probability of insulin icodec being associated with clinically significant or severe hypoglycemia at week 52 was 50% to 80% higher, depending on the analysis method. These higher incidences were observed regardless of whether hypoglycemic events were actively captured using a blood glucose meter or passively captured using a CGM device, and were evident whether data were assessed by event rate or incidence rate. The period of highest hypoglycemia risk occurred between days 2 and 4, coinciding with the peak glucose-lowering phase of this long-acting insulin analog.

Icodec Rejected

Despite the significant potential advantage of reduced injection frequency, the FDA advisory committee concluded that the potential benefits of icodec do not outweigh its risks.

Matthew Drake, Associate Professor at Mayo Clinic College of Medicine, voted against icodec at the meeting. He stated, "The standard therapy insulin degludec has a good safety profile, and compared to it, icodec represents only an incremental improvement." Drake believes that icodec would need additional conditions to potentially gain regulatory approval, such as requiring continuous glucose monitoring (CGM). This is because the patients most likely to benefit from icodec are also the ones least likely to regularly monitor their blood sugar, making the risk of potential hypoglycemic side effects more pronounced in these populations.

Patient representative Paul Tibbits Jr., who voted in favor of insulin icodec, stated that he believed icodec "could be approved" but must come with "serious warnings." For instance, the label should include a requirement for CGM use, exclude patients with "hypoglycemia unawareness (a common phenomenon in diabetes where patients do not perceive or feel symptoms of low blood sugar)," and prohibit the use of the drug by patients in their first year of diabetes. Tibbits Jr. remarked, "As a patient advocate, I certainly want to help people with diabetes, but I also don't want to harm them. I believe this product has the potential to do both."

In order to minimize the risk of hypoglycemia while maintaining a once-weekly injection schedule, Novo Nordisk recommends labeling insulin icodec to inform prescribers and patients about the risk of hypoglycemia.

Relevant tag proposals include:

Restricted to type 1 diabetes patients who wear continuous glucose monitoring (CGM) devices, with a coefficient of variation (CV) ≤36% prior to initiating insulin icodec, and without a history of recurrent severe hypoglycemia or hypoglycemia unawareness.

It is recommended to discontinue the product in patients experiencing recurrent hypoglycemic episodes.

Inform patients and prescribers that the maximum glucose-lowering effect of insulin icodec occurs between the 2nd and 4th days after weekly injection.

FDA Ultimately Made the Same Decision as the Advisory Committee, Rejecting Icodec. In its statement, the FDA indicated that additional requests for information regarding the manufacturing process and insulin use of icodec have been made. Novo Nordisk anticipates that it is unlikely to meet these information requirements set by the FDA this year.

Even though Novo Nordisk's current focus has shifted from insulin products to GLP-1 products, the FDA's rejection is still a significant blow to Novo Nordisk. Its direct competitor in the insulin market, Eli Lilly, is also developing an insulin product that is administered once a week.

Weekly insulin will be more convenient than the currently available daily insulin. The downside is that because it lasts a long time in the body, patients won't be able to flexibly adjust it according to their insulin needs. Type 1 patients, whose bodies do not produce naturally occurring insulin, may especially need this capability. Too much exogenous insulin carries a risk of hypoglycemia.

Six Phase 3 trials show Novo Nordisk's weekly insulin non-inferior to daily insulin products. Trials in type 2 patients did not show a significant difference in hypoglycemia events between icodec and daily insulin, but trials in type 1 patients indicated a higher rate of hypoglycemia among those taking icodec.

Icodec has been approved in multiple regions worldwide, including Europe and Canada, for both type 1 and type 2 diabetes, and in China for type 2 diabetes. Additionally, Lilly is continuing several phase 3 trials of its weekly insulin, with results expected to be announced later this year.

(Source: Shell Society)

03

Bayer's Structure in China to Be Adjusted

Bayer's adjustments continue, and now there is new news from the China region.

Recently, according to reports from multiple media outlets, under the new DSO operational model, Bayer China will form five business segments and six functional departments.

The five major business departments include:

Core Product Business Team: Responsible for the commercial operations of Verquvo, Adalat, Xarelto, Aspirin, Nimotop, Avelox, and Kogenate; Cardiovascular, Renal and Metabolic Business Team: Responsible for the commercial operations of Kerendia and Hua Tang Ning; Women's Health Business Team: Responsible for the commercial operations of all women's health products across all channels; Specialty Medicine Business Team: Responsible for the commercial operations of Eylea and the entire oncology portfolio; Retail Business Team: Responsible for the commercial operations of all Bayer prescription products in the retail channel.

The six major functional departments include:

Strategic Planning and DSO Transformation, Medical Affairs, Market Access, Dealer Management, Business Operation Excellence, Digital Innovation Team.

China is one of the key regions for Bayer's development. According to the 2023 annual report, Bayer's revenue in China reached 3.624 billion euros, accounting for approximately 7.6% of the total revenue in 2023.

At the beginning of this year, Bayer launched a new operating model called "Dynamic Shared Ownership" (DSO) worldwide, aiming to address issues such as hierarchical layers, relative independence between departments, and low operational efficiency.

Back when Bayer announced its first-quarter results, Bayer CEO Bill Anderson pointed out, "Focusing on the implementation of the new DSO (Dynamic Shared Ownership) operating model, Bayer is consolidating responsibilities and building teams to have a greater impact while reducing hierarchy."

Nowadays, the DSO operation model is helping Bayer China restructure. According to the "Pharmaceutical Representative" news, Bayer China began adjustments in June. After the new organizational structure is determined, the selection results of relevant personnel at all levels in each business department will be announced successively and will be fully completed by the end of September this year.

Personnel Adjustment, Strategic Focus Determined

The DSO operation model implemented by Bayer reduces redundant management levels. In addition to structural adjustments, it also involves personnel adjustments and will continue until 2025.

As early as May this year, when Bayer disclosed its first-quarter report, it announced a slight decrease in sales and a workforce reduction of approximately 1,500 employees, most of whom held management positions, while also lowering its full-year profit forecast.

Anderson believes that the reduction in workforce will help Bayer achieve its goal of continuously saving 500 million euros (approximately 540 million US dollars) in costs by 2024 and 2 billion euros (approximately 2.18 billion US dollars) in costs by 2026.

Earlier this March, Bayer streamlined its executive team, reducing the number of senior positions from 14 to 8.

The move to cut jobs dates back to after the Q3 2023 earnings report, when Bayer stated it was considering a spin-off and restructuring of its three major business divisions—pharmaceuticals, consumer health, and crop science—along with significant job reductions. At that time, the relevant industry association (IG BCE - The Mining, Chemical and Energy Industrial Union) opposed the plan due to concerns that many Germans might become unemployed as a result.

The DSO operation model is still ongoing, and there may be further adjustments to relevant personnel by Bayer in the future.

Bayer's business mainly consists of three segments: Crop Science, Pharmaceuticals, and Consumer Health. The 2023 financial report shows that Bayer Group's sales were 47.637 billion euros, a year-on-year decrease of 1.2% (at constant exchange rates). Among them, the Crop Science division's sales decreased by 3.7% to 23.27 billion euros; the Pharmaceuticals division's sales remained flat year-on-year at 18.081 billion euros; the Consumer Health division's sales increased by 6.3% to 6.027 billion euros.

As an important segment of Bayer — crop science, has been entangled in related litigations in recent years, with potential risks still looming; the pharmaceutical business is also showing signs of weakness, as its key products such as rivaroxaban and aflibercept are successively facing patent cliffs, while products like Moxifloxacin and Glucobay have gradually entered centralized procurement.

Whether the staff reduction can help Bayer achieve a rebirth remains uncertain. However, Anderson stated in March this year that over the next 24 to 36 months, Bayer will focus on building a strong pharmaceutical pipeline, resolving litigations, reducing debt, and reforming its operational model.

Large MNCs Adjust While Seeking New Growth

MNCs like Bayer that are restructuring and streamlining staff are not few. This year, AstraZeneca, Pfizer, and others have been adjusting their structures to seek new development.

According to incomplete statistics, Pfizer has carried out five rounds of layoffs and job adjustments globally only in the first half of this year. This includes the closure of oncology research operations in Colorado in April, as well as the completion of the acquisition of Seagen in December last year, and proposed staff reductions in May.

The reasons for personnel adjustments in multinational pharmaceutical companies are varied, including failures in R&D pipelines, closure of related businesses, or even bankruptcy. Regardless of the reasons, these decisions are based on what they consider suitable for their current development.

AstraZeneca China recently split and reorganized its county-level oncology team, integrating it into the Lung Cancer Business Unit and the Urology, Gynecology, and Women's Oncology Business Unit; earlier this year, AstraZeneca announced organizational restructuring and senior management changes, establishing its China pharmaceuticals business and adjusting related senior management positions.

Based on the Q1 reports released by MNCs this year, pharmaceutical companies such as Sanofi, Johnson & Johnson, and Roche have all announced pipeline adjustments, with multiple R&D projects being cut.

As domestic pharmaceutical companies continue to mature, the gap between them and multinational pharmaceutical companies is narrowing. In order to maintain a leading position in the relevant drug market, multinational pharmaceutical companies must formulate new strategies and approaches. Based on this, quite a few MNCs have adjusted their development plans.

Looking back at the past development, cutting pipelines, adjusting the structure in China, and "slimming down" have become commonplace, and these changes are still ongoing among MNCs.

(Source: CPhI China)