Insulin Icodec: First Approval.

Insulin icodec (AWIQLI®) is an ultra-long-acting basal insulin analogue that is being developed by Novo Nordisk for the treatment of diabetes mellitus. Administered once weekly as a subcutaneous injection, insulin icodec is designed to improve treatment adherence and glycaemic control relative to once-daily insulin analogues. On 7 March 2024, insulin icodec was approved in Switzerland for the treatment of diabetes mellitus in adults. Insulin icodec was approved in Canada on 12 March 2024 for the once-weekly treatment of adults with diabetes mellitus to improve glycaemic control and received EU approval in May 2024 for the treatment of diabetes mellitus in adults. This article summarizes the milestones in the development of insulin icodec leading to this first approval for diabetes mellitus.

AVT04: An Ustekinumab Biosimilar.

AVT04 (Uzpruvo®) is a biosimilar of the reference anti-interleukin (IL)-12 and IL-23 monoclonal antibody ustekinumab. It is approved in the EU for plaque psoriasis, paediatric plaque psoriasis, psoriatic arthritis and Crohn's disease as per the reference product. AVT04 has similar physicochemical characteristics to those of reference ustekinumab, and the pharmacokinetic similarity of the agents has been shown in healthy volunteers and patients with moderate to severe chronic plaque psoriasis. AVT04 demonstrated clinical efficacy similar to that of reference ustekinumab in patients with moderate to severe chronic plaque psoriasis, and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of AVT04 were similar to those of reference ustekinumab, and switching from reference ustekinumab to AVT04 had no impact on efficacy, safety or immunogenicity. The role of reference ustekinumab in the management of inflammatory diseases is well established and AVT04 provides an effective biosimilar alternative for patients requiring ustekinumab therapy.

Zastaprazan: First Approval.

Zastaprazan (JAQBO®) is a next-generation potassium-competitive acid blocker being developed by Onconic Therapeutics, a subsidiary of Jeil Pharmaceutical, for the treatment of acid-related diseases. Zastaprazan binds directly to proton pumps in a competitive manner to reduce gastric acid secretion, allowing for a quick onset of action. On 24 April 2024, zastaprazan received approval in South Korea for the treatment of erosive gastroesophageal reflux disease (GERD). Zastaprazan is also undergoing phase III development for the treatment of gastric ulcer and for the prevention of non-steroidal anti-inflammatory drug (NSAID)-induced peptic ulcer. This article summarizes the milestones in the development of zastaprazan leading to this first approval for erosive GERD.

Relugolix/Estradiol/Norethisterone Acetate: A Review in Endometriosis-Associated Pain.

An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate [Myfembree® (USA); Ryeqo® (EU)] (hereafter referred to as relugolix combination therapy) has been approved in the USA for the management of moderate to severe pain associated with endometriosis in premenopausal women and in the EU for the symptomatic treatment of endometriosis in adult women of reproductive age with a history of previous medical or surgical treatment for their endometriosis. The gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix decreases estradiol and progesterone levels, while the addition of estradiol/norethisterone acetate mitigates hypoestrogenic effects including bone mineral density (BMD) loss and vasomotor symptoms. In two pivotal phase III trials, relugolix combination therapy significantly improved dysmenorrhoea and non-menstrual pelvic pain in premenopausal women with moderate to severe endometriosis. The combination also reduced overall pelvic pain and dyspareunia, reduced analgesic and opioid use, and improved health-related quality of life. The efficacy of relugolix combination therapy was sustained over the longer term (up to 2 years). Relugolix combination therapy was generally well tolerated and BMD loss over time was minimal. With the convenience of a once daily oral dosing regimen, relugolix combination therapy is a valuable addition to the options currently available for the management of endometriosis-associated pain.

Endometriosis is a disease where tissue similar to the lining of the uterus grows outside the uterus and may reach other organs. This causes chronic pain as a result of increased inflammation and scar tissue. Women with endometriosis may experience painful menstrual periods, pelvic pain between periods, pain during sex, painful bowel movements and painful urination. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone (also known as norethindrone) acetate [Myfembree^® (USA); Ryeqo^® (EU)] (hereafter referred to as relugolix combination therapy) has been approved to treat endometriosis-associated pain. The treatment works by decreasing levels of ovarian hormones (estrogen and progesterone). In clinical trials, relugolix combination therapy improved period pain and pain between periods in women with moderate to severe pain associated with endometriosis. The treatment also improved other symptoms (overall pelvic pain and pain during sex), reduced the need for pain medications and improved health-related quality of life. Relugolix combination therapy was generally well tolerated and caused minimal bone loss, which is known to occur with some hormone therapies. With the convenience of a once daily oral pill, relugolix combination therapy is a valuable addition to the options currently available for women with endometriosis-associated pain.

SER-109 (VOWST™): A Review in the Prevention of Recurrent Clostridioides difficile Infection.

SER-109 (VOWST™; fecal microbiota spores, live-brpk) is a live biotherapeutic product indicated to prevent the recurrence of Clostridioides difficile infection (CDI) in patients 18 years of age and older following standard of care (SOC) antibacterial treatment for recurrent CDI. It is a purified bacterial spore suspension sourced from healthy donors. As the first oral faecal microbiota product approved for prevention of recurrent CDI, SER-109 is administered as four capsules once daily for three consecutive days. In a well-designed, placebo-controlled, phase III trial (ECOSPOR III), SER-109 significantly reduced the risk of recurrent CDI at 8 weeks post-treatment, with a durable response seen at 6 months post-treatment. Treatment with SER-109 was also associated with rapid and steady improvement in health-related quality of life compared with placebo. SER-109 was generally well tolerated, with a safety profile similar to that of placebo. The most common adverse events were of mild to moderate severity and generally gastrointestinal in nature. Thus, with the convenience of oral administration and lack of necessity for cold storage, SER-109 is a valuable option for preventing further CDI recurrence in adults following antibacterial treatment for recurrent CDI.

Clostridioides difficile is a type of bacteria that can produce toxins leading to infection of the large intestine. Symptoms of C. difficile infection (CDI) range from mild diarrhoea to severe life-threatening sepsis. Treatment is usually antibiotics to kill the toxin-producing bacteria and resolve symptoms. However, antibiotics can disrupt the gut microbiota and leave individuals at risk of CDI recurrence. SER-109 (VOWST^™; fecal microbiota spores, live-brpk) is a microbiome therapy containing purified live bacterial spores extracted from donated human faecal matter intended to repair the microbiome. It is given as four oral capsules per day over three consecutive days to prevent the recurrence of CDI in adults following standard antibiotic treatment. In a phase III clinical trial, patients with recurrent CDI who received SER-109 had a significantly lower rate of CDI recurrence at 8 weeks than those who received placebo, and this response was sustained through 6 months. SER-109 was generally well tolerated, and most adverse events were mild or moderate in severity. With the convenience of oral administration and no refrigeration requirements, SER-109 is a valuable option for preventing further CDI recurrence in adults who have received antibiotics for recurrent CDI.

Tremelimumab: A Review in Advanced or Unresectable Hepatocellular Carcinoma.

Tremelimumab (tremelimumab-actl; Imjudo®) is a monoclonal antibody and immune checkpoint inhibitor (ICI) that blocks cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). A single, priming dose of intravenous tremelimumab is used in combination with durvalumab, an ICI that blocks programmed cell-death ligand 1, in a regimen known as STRIDE (Single Tremelimumab Regular Interval Durvalumab). STRIDE is approved for the treatment of adults with unresectable hepatocellular carcinoma (HCC) in the USA and Japan and for the first-line treatment of adults with advanced or unresectable HCC in Europe. In the phase III HIMALAYA trial, STRIDE significantly improved overall survival (OS) compared with sorafenib in adults with unresectable HCC and no prior systemic therapy. A higher proportion of STRIDE versus sorafenib recipients had an objective response to treatment. The OS benefit associated with STRIDE was sustained with 4 years' follow-up. STRIDE had a manageable safety profile that differed from that of sorafenib. Grade 3 or 4 treatment-related adverse events occurred in a lower proportion of STRIDE versus sorafenib recipients. Based on the available evidence, tremelimumab used as part of the STRIDE regimen is a valuable first-line agent that expands the treatment options available to patients with advanced or unresectable HCC.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer death worldwide. HCC is commonly associated with cirrhosis linked to chronic viral hepatitis and non-alcoholic fatty liver disease. Tremelimumab (tremelimumab-actl; Imjudo^®) is a type of immunotherapy that helps the body's immune system attack HCC cells by binding to and blocking the action of an immune-checkpoint protein called cytotoxic T lymphocyte-associated antigen-4. A single dose of intravenous tremelimumab is used in combination with treatment with durvalumab, in a regimen known as STRIDE (Single Tremelimumab Regular Interval Durvalumab), for adults with unresectable HCC in the USA and Japan and as a first-line treatment for adults with advanced or unresectable HCC in the EU. In patients with unresectable HCC, STRIDE improved overall survival more than sorafenib, including at 4 years' follow-up. A higher proportion of patients responded to treatment with STRIDE compared with sorafenib. STRIDE had manageable adverse events. Tremelimumab used as part of the STRIDE regimen is a valuable first-line agent that expands the treatment options available to patients with HCC that is advanced or unable to be removed with surgery.

Befotertinib: First Approval.

Befotertinib (Surmana®) is an orally administered, highly selective, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) being developed by Betta Pharmaceuticals and InventisBio for the treatment of non-small cell lung cancer (NSCLC). In May 2023, befotertinib was approved in China for the second-line treatment of patients with locally advanced or metastatic NSCLC who have received EGFR TKI therapy and have disease progression with positive EGFR T790M mutation. Befotertinib is under regulatory review for the first-line treatment of NSCLC in China. Clinical studies assessing befotertinib as an adjuvant therapy after surgery for early EGFR-mutant NSCLC (phase III) and in combination with icotinib for advanced or metastatic EGFR-mutant NSCLC (phase II) are currently underway in China. This article summarizes the milestones in the development of befotertinib leading to this first approval for the second-line treatment of EGFR T790M-mutated locally advanced or metastatic NSCLC.

Remdesivir: A Review in COVID-19.

Remdesivir (Veklury®), a nucleotide analogue prodrug with broad-spectrum antiviral activity, is approved for the treatment of coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 infection. Unlike some antivirals, remdesivir has a low potential for drug-drug interactions. In the pivotal ACTT-1 trial in hospitalized patients with COVID-19, daily intravenous infusions of remdesivir significantly reduced time to recovery relative to placebo. Subsequent trials provided additional support for the efficacy of remdesivir in hospitalized patients with moderate or severe COVID-19, with a greater benefit seen in patients with minimal oxygen requirements at baseline. Clinical trials also demonstrated the efficacy of remdesivir in other patient populations, including outpatients at high risk for progression to severe COVID-19, as well as hospitalized paediatric patients. In terms of mortality, results were equivocal. However, remdesivir appeared to have a small mortality benefit in hospitalized patients who were not already being ventilated at baseline. Remdesivir was generally well tolerated in clinical trials, but pharmacovigilance data found an increased risk of hepatic, renal and cardiovascular adverse drug reactions in the real-world setting. In conclusion, remdesivir represents a useful treatment option for patients with COVID-19, particularly those who require supplemental oxygen.

Coronavirus disease 2019 (COVID-19) was first reported in China in 2019 and quickly spread around the world. The symptoms of COVID-19 can vary from person to person, with some people having no symptoms and others becoming very unwell. Most patients with COVID-19 can treat their symptoms at home, but some patients may be admitted to hospital and/or treated with specialized medications such as remdesivir (Veklury^®). Remdesivir is an antiviral medicine that can reduce the amount of virus that causes COVID-19. It is given once a day, usually for 5­10 days, as an intravenous infusion. Remdesivir has been shown to improve the recovery time in hospitalized patients with COVID-19, including children and adolescents. It may also reduce the risk of death in hospitalized patients who are not being ventilated before they start treatment. A 3-day course of remdesivir is also effective in patients whose age or underlying health puts them at high risk for becoming severely ill. The drug is generally well tolerated. Therefore, remdesivir is a useful treatment option for patients with COVID-19, especially those who require additional oxygen.

Ritlecitinib: First Approval.

Ritlecitinib (LITFULO™), an orally administered kinase inhibitor, is being developed by Pfizer for the treatment of alopecia areata, vitiligo, ulcerative colitis and Crohn's disease. On 23 June 2023, ritlecitinib received approval in the USA for the treatment of severe alopecia areata in adults and adolescents 12 years and older. Ritlecitinib was approved in Japan on 26 June 2023 for the treatment of alopecia areata (limited to intractable cases involving widespread hair loss). Ritlecitinib has also received a positive opinion in the EU and is under regulatory review in the UK and China. This article summarizes the milestones in the development of ritlecitinib leading to this first approval for severe alopecia areata.

Tofersen: First Approval.

Tofersen (Qalsody™) is an antisense oligonucleotide being developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS). On 25 April 2023, tofersen was approved in the USA for the treatment of ALS in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This article summarizes the milestones in the development of tofersen leading to this first approval for ALS.

Efbemalenograstim Alfa: First Approval.

Efbemalenograstim alfa (Ryzneuta®) is a subcutaneously administered recombinant fusion protein that is being developed by Evive Biotech for the management of chemotherapy-induced neutropenia. On 6 May 2023, efbemalenograstim alfa was approved in China for reducing the incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignant tumours who are treated with myelosuppressive anticancer drugs that are prone to cause febrile neutropenia. Efbemalenograstim alfa is under regulatory review for the management of chemotherapy-induced neutropenia in the EU and the USA. This article summarizes the milestones in the development of efbemalenograstim alfa leading to this first approval for the management of chemotherapy-induced neutropenia.

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer.

Trastuzumab deruxtecan (Enhertu®) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate approved in several countries, including the USA and those of the EU, for adults with unresectable or metastatic HER2-positive breast cancer who have previously received at least one prior anti-HER2-based regimen. In a pivotal phase 3 trial in this setting, intravenous trastuzumab deruxtecan demonstrated prolonged progression-free survival compared with trastuzumab emtansine (previously the recommended second-line therapy in this indication). Trastuzumab deruxtecan had a generally manageable safety and tolerability profile. Common treatment-related adverse events included haematological and gastrointestinal disorders. Interstitial lung disease (ILD)/pneumonitis is associated with a regulatory warning and requires careful monitoring. In conclusion, trastuzumab deruxtecan is a valuable new treatment option for HER2-positive breast cancer, having been shown to be effective with a generally manageable safety and tolerability profile in adults with unresectable or metastatic disease who have received one or more prior anti-HER2-based regimens.

Human epidermal growth factor receptor 2 (HER2)-targeted therapies have improved HER2-positive breast cancer outcomes in recent years. Despite this, almost all patients will eventually experience disease progression (cancer growth or spread). Trastuzumab deruxtecan (Enhertu^®) is an intravenously administered treatment that combines a drug that is toxic to cells and an antibody that targets it to HER2-expressing cells. It has been approved in several countries for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have previously received one or more anti-HER2-based therapies. In a pivotal clinical trial, trastuzumab deruxtecan showed longer survival without disease progression than trastuzumab emtansine (the previously recommended treatment after first disease progression). Trastuzumab deruxtecan had a generally manageable safety and tolerability profile. The most common classes of adverse events were blood and gastrointestinal disorders. Fatal events of interstitial lung disease (ILD)/pneumonitis have occurred with trastuzumab deruxtecan and patient monitoring is required. Trastuzumab deruxtecan is a valuable new option for patients with unresectable or metastatic HER2-positive breast cancer who have received at least one prior anti-HER2-based regimen.

Cipaglucosidase Alfa: First Approval.

Cipaglucosidase alfa (Pombiliti™) is a recombinant human acid α-glucosidase (GAA) product being developed by Amicus Therapeutics along with the enzyme stabilizer miglustat as a two-component therapy for Pompe disease. Pompe disease is a rare, inherited lysosomal disease caused by a deficiency of the enzyme GAA, which leads to accumulation of glycogen in various tissues. On 27 March 2023, cipaglucosidase alfa was approved in the EU as a long-term enzyme replacement therapy (ERT) used in combination with miglustat for the treatment of adults with late-onset Pompe disease. This article summarizes the milestones in the development of cipaglucosidase alfa leading to this first approval.

Rimegepant: A Review in the Acute Treatment and Preventive Treatment of Migraine.

Rimegepant [Nurtec® ODT (USA); Vydura® (EU)] is a calcitonin gene-related peptide (CGRP) receptor antagonist approved for the acute treatment of migraine with or without aura in adults, and for the preventive treatment of episodic migraine in adults. Rimegepant is available as an orally disintegrating tablet (ODT), which offers convenience and a potentially faster response time than the conventional tablet formulation. In pivotal phase III trials, rimegepant was more effective than placebo at relieving pain and the most bothersome symptom when taken as needed for the acute treatment of migraine. Rimegepant was also more effective than placebo at reducing the number of monthly migraine days when taken every other day for the preventive treatment of migraine. The beneficial effects of rimegepant in reducing migraine frequency and improving quality of life were maintained over the longer term (up to 52 weeks). Rimegepant was generally well tolerated, with no evidence of hepatotoxicity or cardiovascular toxicity in clinical trials. As the first dual agent approved for both treatment and prevention of migraine, rimegepant represents a useful option for the management of migraine in adults.

Migraine is a type of headache that causes severe throbbing pain, usually on one side of the head. Bothersome symptoms that may occur during a migraine include nausea, vomiting and sensitivity to light and sound. Medications for migraine are aimed at stopping symptoms (acute treatment) and/or reducing the frequency of future attacks (preventive treatment). Calcitonin gene-related peptide (CGRP) is a protein that is released during migraine attacks, causing inflammation and activation of other pathophysiological processes responsible for pain. Rimegepant [Nurtec^® ODT (USA); Vydura^® (EU)] is an oral medication that works by blocking the CGRP receptors. A convenient quick-dissolve tablet formulation is available that can be placed on or under the tongue and swallowed without water. Rimegepant relieves pain and bothersome symptoms when taken as needed for a single migraine attack, and reduces the number of migraine days per month when taken every other day to prevent migraine. Rimegepant is generally well tolerated. As the first medication approved to both treat acute migraine attacks and help prevent future attacks, rimegepant represents a useful treatment option for patients with migraine.

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence.

Abemaciclib [Verzenio® (USA) or Verzenios® (EU)] is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved in combination with adjuvant endocrine therapy for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive, early breast cancer with a high risk of recurrence. In a phase III trial, abemaciclib plus endocrine therapy reduced the risk of recurrence of breast cancer compared with endocrine therapy alone, including in patients who had previously received neoadjuvant chemotherapy, in patients with high- and low-scoring Ki-67 tumours, and in both premenopausal and postmenopausal patients. The tolerability profile of abemaciclib plus endocrine therapy was acceptable and manageable, with diarrhoea, infections and neutropenia being the most common adverse events. Thus, abemaciclib in combination with standard endocrine therapy is a valuable additional treatment option for patients with HR+, HER2-, node-positive early breast cancer with a high risk of recurrence.

In patients with hormone receptor positive (HR+) cancers, endocrine therapy is often used to reduce the risk of breast cancer recurrence after successful initial treatment; however, in a subset of patients, recurrence rates can remain high. In a pivotal phase III trial, the addition of abemaciclib [Verzenio^® (USA) or Verzenios^® (EU)] to standard endocrine therapy significantly reduced the rate of breast cancer recurrence compared with endocrine therapy alone in patients with HR+, human epidermal growth factor receptor 2 negative (HER2−), node-positive early breast cancer who were at a high risk of recurrence. Benefit was seen in both patients with characteristics that are associated with higher risk (premenopausal, high Ki-67 scores, previously received neoadjuvant chemotherapy) and comparatively lower risk of recurrence (postmenopausal, low Ki-67 scores). Diarrhoea, infections and neutropenia were the most common adverse events in patients receiving abemaciclib plus endocrine therapy. The overall tolerability of abemaciclib was acceptable. The addition of abemaciclib to endocrine therapy is a valuable therapeutic option for adjuvant therapy in high-risk patients with HR+, HER2−, node-positive early breast cancer.