Sanofi’s Rare Disease Drug Xenpozyme’ Approval; FDA Approves Novartis’ Pluvicto; AstraZeneca’s Imfinzi Trial Result; FDA’s Green Signal to Argenx’ Vyvgart; ViiV Healthcare and J&J’s HIV Treatment Cabenuva; UCB’s FINTEPLA Approval; Cullinan’s Update for CLN-081; MEI Pharma & Kyowa’s Zandelisib Approval

Sanofi’s Rare Disease Drug Xenpozyme Wins World’s First Approval in Japan

Sanofi’s Xenpozyme, also known as olipudase alfa, the world’s first therapy for the rare disease Niemann-Pick type A/B and B, has been approved for the treatment of children and adults with non-CNS manifestations of Acid Sphingomyelinase Deficiency (ASMD) by Japan’s drug regulator. Sanofi hopes to receive approvals for the drug in the United States and Europe before the end of the year. Xenpozyme is a recombinant human Acid Sphingomyelinase (ASM) enzyme designed to replace deficient or defective ASM. It is only approved in Japan for the treatment of ASMD types A/B and B, and it has not been studied in ASMD type A.

The Japanese Ministry of Health, Labor, and Welfare made its decision based on findings from Sanofi’s ASCEND and ASCEND-Peds studies, which showed that Xenpozyme improved lung function while decreasing spleen and liver volumes. Sanofi revealed in early 2020 that in the 36-subject Phase 2/3 ASCEND trial in adults, patients who received biweekly infusions of Xenpozyme for a year experienced a 22% improvement from baseline in a measure of lung function versus a 3% improvement in the placebo arm. Meanwhile, Xenpozyme patients’ spleen volumes decreased by 39.5% over the course of the trial, compared to a 0.5% increase in the control cohort.

In addition, the Phase 2 ASCEND-Peds study assessed Xenpozyme’s safety and tolerability in children. The findings of that study were a little murkier, with three patients experiencing five treatment-related serious adverse events between them—though none of those reactions resulted in a patient permanently discontinuing participation in the trial, according to Sanofi in 2020. Now that Xenpozyme has received its first approval, Sanofi’s next goal is to rush this important medicine to ASMD patients around the world.

AstraZeneca’s Imfinzi Fails in Phase 3 Cervical Cancer Trial

AstraZeneca’s hopes of developing Imfinzi, a PD-L1 inhibitor, for Cervical Cancer have been dashed by a failed Phase 3 trial of the drug in combination with chemotherapy as a first-line treatment for women with locally advanced tumors.

The CALLA trial compared Imfinzi (durvalumab) with chemoradiotherapy (CRT) to CRT alone in an all-comer Cervical Cancer population, regardless of PD-L1 biomarker status, with the goal of extending the use of immunotherapy in this type of cancer.

Cervical Cancer is one of the most prevalent cancers in women, with 14,500 new cases diagnosed each year and 4,300 deaths in the United States. Despite advances in Cervical Cancer prevention and screening, it remains a major public health concern, disproportionately affecting young and middle-aged women, with a five-year survival rate of 40% for locally advanced (stage 3) tumors.

Currently, only Merck & Co’s PD-1 inhibitor Keytruda (pembrolizumab) has been approved for Cervical Cancer since 2018, and specifically for patients whose tumors express the PD-L1 biomarker at a level of 1% or higher. It’s a setback for AstraZeneca, which is attempting to expand Imfinzi’s uses beyond its current approved indications in Non-small Cell Lung Cancer and Small Cell Lung Cancer (SCLC), which generated USD 2.4 billion of revenue for the company in 2021. It had hoped to file for Imfinzi approval based on the CALLA results later this year, and it currently has no other late-stage Cervical Cancer studies.

FDA Approves Novartis’ Pluvicto, First Radioligant for Prostate Cancer

In one of the latest clinical development in the mCRPC therapeutics domain, Novartis has announced that it has received US FDA approval for the Pluvicto (lutetium Lu 177 vipivotide tetraxetan) for the treatment of certain type of advanced cancer called prostate-specific membrane antigen–positive metastatic castration-resistant prostate cancer (PSMA-positive mCRPC) in adult patients. The drug was formerly referred to as 177Lu-PSMA-617. The approval of the therapy is expected to significantly improve survival rates for mCRPC patients who are currently facing limited treatment options. Pluvicto is anticipated to hit the market in a few weeks.

The approval of Pluvicto is based on the phase 3 VISION (NCT03511664) trial result that evaluated the effectiveness and safety profile of the drug. The trial presented statistically significant improvement in the primary endpoints of overall survival (OS) and radiographic progression-free survival (rPFS). Pluvicto is the first FDA-approved targeted radioligand therapy (RLT) for eligible patients with mCRPC. It combines a targeting compound (ligand) with a therapeutic radioisotope (a radioactive particle). 

Prostate cancer is one of the most common types of cancer in males and also the second leading cancer after skin cancer.  In the US, nearly 1 in 9 men are diagnosed with prostate cancer at some point in their lives. It is the second leading cause of cancer death in US men, behind only lung cancer. As per DelveInsight, the total Prostate Cancer prevalent cases in the 7MM were observed to be approx. 6,742,300+ cases in 2017, and are expected to increase during the study period (2019–2032). Additionally, the total Metastatic Castration-Resistant Prostate Cancer (mCRPC) cases in the 7MM were found to be approx. 77,300+ in 2017. Similarly, in the United States, there were 33,800+ cases of mCRPC in 2017, which are estimated to increase in the coming years.

FDA Approves UCB’s Drug for Rare Childhood Epilepsy

The US FDA has approved UCB’s Drug FINTEPLA® (fenfluramine) Oral Solution to treat seizures associated with Lennox-Gastaut Syndrome (LGS), a rare form of childhood epilepsy. The FDA approval was based on the safety and efficacy data from a Phase 3 clinical trial result in 263 patients with LGS (age 2-35 years). Fenfluramine demonstrated efficacy in the most difficult to treat seizure types 1 & 2 including drop seizures.

The therapy has already been approved in the US for the treatment of Dravet syndrome (DS), another form of childhood-onset epilepsy, in patients aged two years and older. It is available in the United States only through a restricted drug distribution program.

The therapy is developed by California-based Zogenix, a company focused on the rare diseases segment. In January 2022, UCB acquired Zogenix in a deal worth about US$ 1.9 billion/ € 1.7 billion. UCB has a strong presence in the epilepsy therapeutics market with several of the drugs in its portfolio. The acquisition has further elevated the UCB’s dominance in the epilepsy domain. 

LGS is a severe life-long disease with wide-ranging effects beyond seizures. The progression of LGS causes cognitive dysfunction and frequent seizures. In nearly, 50 per cent of cases, behavioral problems including hyperactivity and aggressiveness are more common. As per DelveInsight, the total Lennox Gastaut Syndrome prevalent population in 7 major markets was estimated to be 111,700+ in 2017. Among all the countries, the estimates show a higher population of LGS in the United States with over 32,000+ cases in 2017. The approval of FINTEPLA is expected to change the treatment scenario for the patients affected with LGS. However, the other major therapies by key companies such as Takeda (soticlestat) and Eisai (lorcaserin and Fycompa) is expected to give tough competition to UCB’s FINTEPLA in the LGS therapeutics market.

FDA’s Green Signal to Argenx’ Subcutaneous Vyvgart for Myasthenia Gravis  

Argenx which is considered to be a global immunology company demonstrated positive topline results from current and ongoing study on the usage of Efgartigimod Alfa/Vyvgart for generalized Myasthenia Gravis treatment. The data was obtained from a Phase III, ADAPT-SC study indicating that VYVGART when administered subcutaneously was found to be as effective as administering in the IV form. It achieved the primary endpoint for reducing levels of malfunctioning IgG (immunoglobulin G) antibodies that cause weakness and fatigue in generalized Myasthenia Gravis (gMG) patients.

In the open-label, randomized, parallel-group Phase III ADAPT-SC trial, almost 110 adult generalized Myasthenia Gravis (gMG) patients were given 1000mg of efgartigimod-PH20 subcutaneously for 21 days. On the other hand, others were administered the drug intravenously (IV) with the dosage of 10mg/kg. Vyvgart’s pharmacodynamic effect was then observed one week after the last subcutaneous or intravenuous dose was administered. The subcutaneous drug is produced by utilizing Halozyme’s ENHANZE drug delivery technology recombinant human hyaluronidase PH20 (rHuPH20).  

Myasthenia Gravis is a very rare and chronic autoimmune disease in which the IgG antibodies disrupt the communication between muscles and nerves, leading to muscle weakness. With this new data in hand, Argenx is anticipated to file for approval of subcutaneous Vyvgart later this year.

FDA provided a green flag for label update to ViiV Healthcare and Johnson & Johnson’s Cabenuva for HIV treatment. The update makes Cabenuva therapy’s oral lead-in tablets optional. It signifies that HIV patients wanting to trade their daily oral doses of antiretroviral therapy (ART) for an injection delivered once a month or every two months will no longer require the transition to oral therapy due to the active ingredients present in Cabenuva which are cabotegravir and rilpivirine. Conclusively, Cabenuva may or may not be taken orally for one month in order to evaluate tolerability before initiating injections of the medication.

Cabenuva was developed with an intent of replacement antiretroviral therapy (ART) for virologically suppressed adults experiencing HIV-1 infection. It is also the first and only complete long-acting HIV treatment regimen approved in the US with either a once-monthly or every 2-month HIV treatment. The latest update approval is done on the basis of the clinical study namely the FLAIR trial, that indicated that similar results were demonstrated on factors of virologic suppression, safety and tolerability, as well as pharmacokinetics in people starting Cabenuva with or without the oral lead-in. The eligible HIV patients previously should have no history of treatment failure and also no known or suspected resistance to cabotegravir or rilpivirine. In the study’s Phase 2 & 3 randomized trials, scientists found out that the monthly injectable combination had comparable results with current daily oral antiretroviral regime.

“Since launching Cabenuva, we have been keenly focused on optimizing the user experience for both people living with HIV and health care providers,” said Lynn Baxter, North American head of ViiV Healthcare.

FDA Rejects MEI Pharma and Kyowa’s Plan for Zandelisib Approval

MEI Pharma, and Kyowa Kirin Co., provided an update after a recent meeting with the FDA to discuss the pursuit of a marketing authorization for Zandelisib, a phosphatidylinositol-3-kinase (PI3K) inhibitor drug candidate, through the accelerated approval pathway under 21 CFR Part 314.500, Subpart H, based on data generated by the single-arm Phase II TIDAL study. In the meeting, the FDA apprized the companies of its position that a randomized trial is now needed to competently assess the drug efficacy and safety of PI3K inhibitor drug candidates, including zandelisib. 

The agency discouraged a filing based on Phase II TIDAL study data found on this view. It emphasized that the companies continue efforts with the ongoing, randomized Phase III COASTAL study. Accordingly, in line with the FDA’s recommendation, the companies do not intend to submit an FDA marketing application based on the single-arm Phase II TIDAL study. Additionally, the FDA declared that the safety on the 60 mg intermittent schedule appears reasonable. It suggested continued dose exploration to further support the current dose and regimen.

“The FDA’s present position on assessing the benefit & risk of PI3K inhibitors is solely based on the single arm studies that appears to have evolved, as evidenced by the position the FDA communicated at the recent meeting on Zandelisib and the upcoming ODAC meeting on April 21, 2022 to discuss whether randomised data should be required for the class of PI3K inhibitors to show appropriate evidence of efficacy & safety,” said Daniel P. Gold, president and chief executive officer of MEI Pharma. 

Zandelisib is a selective PI3Kδ inhibitor and an investigational cancer treatment being developed as an oral, once-daily treatment for patients with B-cell malignancies. Clinical trials examine the safety & efficacy of zandelisib as a single agent and other modalities while administered on an Intermittent Dosing Regimen (IDT). 

Cullinan Oncology Announces Clinical and Regulatory Update for CLN-081

Cullinan Oncology, a biopharmaceutical company focused on developing a varied pipeline of targeted therapies for cancer patients, announced clinical and regulatory updates on CLN-081. CLN-081 is being assessed in an ongoing Phase 1/2a clinical trial in patients suffering with Non-small Cell Lung Cancer whose tumors harbour epidermal growth factor receptor exon 20 insertion mutations that have advanced on or after the prior therapy. CLN-081 is an irreversible, orally accessible EGFR inhibitor that targets cells with EGFR exon 20 insertion mutations while preserving cells with wild type EGFR. In a Phase 1/2a trial, Cullinan is testing different doses of CLN-081 in patients suffering from non-small cell lung cancer who have EGFR exon 20 mutations and have previously undergone treatment.

Clinical Update: In the ongoing Phase 1/2a study, CLN-081 was conducted orally at different dose levels including 30mg, 45mg, 65mg, 100mg and 150 mg twice daily (BID). The most recent data include 39 patients treated at 100 mg BID following the addition of 3 patients who were reassigned to receive the 100 mg BID dose after enrollment at 150 mg BID was discontinued.

Out of 39 evaluable response patients, 16 achieved a confirmed partial response for a 41% confirmed response rate. No patients have experienced Grade 3 or more significant treatment-related diarrhoea or rash. Good response durability was previously observed in the initial phase I patient cohort (n=13) with an estimated median response duration > 15 months and median progression-free survival of 12 months.

Regulatory Update: CLN-081 was recently granted Breakthrough Therapy Designation by the Food and Drug Administration. The FDA encouraged Cullinan to explore the possibility of a food effect on the clinical profile of the 150mg dose, as part of its Project Optimus initiative for dose optimization. CLN-081 was administered under fasting conditions under the ongoing Phase 1/2a trial. The FDA has approved Cullinan’s plan to conduct a small food effect study designed to evaluate food’s potential impact on exposure and other pharmacokinetic parameters at 150mg. Cullinan expects to start a pivotal study in the second half of 2022 following the completion of this PK food effect study.