Due to the advanced age and comorbidities at the time of diagnosis, many patients are not deemed eligible for intensive and potentially curative therapies. Despite advances in available care, the estimated 5-year survival for patients in the United States with AML remains only 31%.
The Orphan Products Development FDA office grants orphan drug designation status to drugs and biologics designed for the safe and effective treatment, diagnosis, and prevention of rare diseases affecting fewer than 2 lakh people in the United States. ODD benefits drug developers designed to support the development of drugs and biologics for small patient populations with unmet medical needs. These benefits include exemptions from specific FDA fees, assistance in the drug development process, tax credits for qualified clinical costs, and seven years of marketing exclusivity.
EU Approves Sanofi’s Xenpozyme for ASMD Treatment
The European Commission approved Xenpozyme as the first and the only enzyme replacement therapy for treating non-Central Nervous System manifestations of Acid sphingomyelinase Deficiency in pediatric and adult patients with acid sphingomyelinase deficiency type A/B or ASMD type B. The approval is established on positive data from the ASCEND and ASCEND-Peds clinical trials, in which Xenpozyme demonstrated substantial and clinically relevant improvement in lung function and reduction of spleen and liver volumes, with a well-tolerated safety profile.
Acid sphingomyelinase deficiency is a sporadic, accelerating genetic disease with significant morbidity and mortality rate, especially among infants and children. Signs and symptoms of acid sphingomyelinase deficiency may include enlarged spleen or liver, difficulty breathing, lung infection, and unusual bruising or bleeding, among other disease manifestations.
Xenpozyme is an enzyme replacement therapy designed to replace deficient/defective acid sphingomyelinase (ASM). ASM is an enzyme that allows for the breakdown of the lipid sphingomyelin. In individuals suffering from ASMD, the insufficient amount of the acid sphingomyelinase enzyme indicates that sphingomyelin is poorly metabolized, possibly leading to lifelong accumulation in the body and can cause organ damage.
Approval is based on positive results from 2 clinical trials in children as well as adults:
ASCEND
The ASCEND trial assessed 36 adult patients with acid sphingomyelinase deficiency type A/B or type B to receive Xenpozyme or placebo for a year to evaluate the efficiency and safety of the drug. The study showed that Xenpozyme improved lung function, assessed as the percent change from baseline to week 52 in predicted lung diffusing capacity for carbon monoxide (DLco), and reduced spleen size, considered as percent change from baseline in multiples of average spleen volume.
- Patients treated with Xenpozyme improved in DLco from baseline to week 52 by 22 percent compared to 3 percent for the patients in the placebo group. The difference between the two treatment arms was statistically significant.
- Patients treated with Xenpozyme reduced spleen size by 39.5% at week 52 compared to an increase of 0.5% for the patients in the placebo group. The difference between the two treatment arms was statistically significant.
- All ASCEND patients treated with Xenpozyme demonstrated improvement in one or both primary endpoints.
The adverse events (AEs) incidence was similar in patients receiving Xenpozyme to that in patients receiving placebo. There were five severe adverse events in the Xenpozyme arm and 11 in the placebo arm, none of which was treatment-related. No adverse events were observed that led to the treatment discontinuation or study withdrawal. The most common adverse events in the ASCEND trial were nasopharyngitis, headache, cough, arthralgia, and upper respiratory tract infection.
ASCEND-Peds
The single-arm ASCEND–Peds trial analyzed 20 pediatric patients with acid sphingomyelinase deficiency type A/B or type B who all acquired Xenpozyme, with the primary objective of evaluating the safety & tolerability of Xenpozyme for 64 weeks. All patients completed the study and continued the extension trial. The ASCEND-Peds study also surveyed efficacy endpoints of progressive lung disease and spleen and liver enlargement. After one year of treatment, the percent predicted DLco mean a rise from baseline was 33 percent in 9 patients who were able to perform the test at baseline. The mean spleen volume drop was 49 percent compared to the baseline.
All ASCEND-Peds patients experienced at least one adverse effect, primarily mild and moderate, over the 64-week treatment period. Five treatment-related severe AEs were observed in three patients: two cases of transient, asymptomatic alanine aminotransferase (ALT) increase in one patient, one point each of urticaria and rash in one patient, and one anaphylactic reaction in one patient. No patients had to discontinue the treatment due to an adverse event permanently. The most common adverse events in the ASCEND-Peds trial were pyrexia, cough, vomiting, nasopharyngitis, diarrhea, headache, upper respiratory tract infection, discoloration, abdominal pain, nasal congestion, rash, urticaria, scratch, and epistaxis.
AstraZeneca’s Imfinzi Shows Positive Results in Late-Stage Lung Cancer Trial
AstraZeneca is attempting to infringe on the domain of Bristol-Myers Squibb, which just received FDA approval for Opdivo as neoadjuvant therapy for non-small cell lung cancer. The AEGEAN study with AstraZeneca’s PD-L1 inhibitor Imfinzi (durvalumab) plus chemotherapy given prior to surgery for resectable NSCLC tumors indicated a significant improvement in the pathologic complete response (pCR) rate when compared to chemo alone. The company stated that it would share interim results from the study with regulators while continuing to follow up with patients to the additional primary objective of event-free survival (EFS), which is still blinded at this time.
If the results are strong enough to gain clearance, Imfinzi will be able to capitalize on the recent approval of Opdivo (nivolumab) in neoadjuvant NSCLC, one of the few immunotherapy areas in this type of cancer that is not dominated by Merck & Co’s rival Keytruda (pembrolizumab). Up to 30% of all NSCLC patients worldwide are discovered early enough to undergo curative surgery. However, only about 56-65% of individuals with Stage II disease will survive for five years. This drops to 24-41% for patients with stage III disease.
Moreover, AstraZeneca is conducting numerous registrational trials in early-stage lung cancer, including resectable NSCLC (ADJUVANT BR.31) and unresectable NSCLC (PACIFIC-2, 4, 5, 8, and 9), as well as limited-stage small cell lung cancer (SCLC) (ADRIATIC).
Imfinzi is approved for the curative-intent treatment of unresectable stage III NSCLC in patients whose disease has not progressed after chemoradiotherapy in the United States, Japan, China, the European Union, and many other countries and is the global standard of care in this setting based on the PACIFIC Phase III trial. Imfinzi is also approved for the advanced-stage SCLC treatment in the United States, the European Union, Japan, China, and other countries based on the CASPIAN Phase III trial.
Novartis Announces Positive Phase III Results of Tislelizumab in Relapsed Oesophageal Cancer
Novartis is still waiting for the FDA to approve its PD-1/PD-L1 inhibitor latecomer tislelizumab in relapsed oesophageal cancer, but it is already planning to shift the drug to first-line treatment. The new phase III findings from the RATIONALE 306 research reveal that tislelizumab plus chemotherapy increased overall survival in previously untreated patients with advanced oesophageal squamous cell carcinoma (ESCC) compared to chemo plus placebo.
Tislelizumab plus chemotherapy resulted in a median OS of 17.2 months (CI, 15.8-20.1 months) versus 10.6 months (CI, 9.3-12.1 months) in patients receiving chemotherapy plus placebo, as well as a 34% reduction in the probability of death (hazard ratio=0.66; CI, 0.54-0.80, p0.0001). These findings were presented in partnership with BeiGene, during a late-breaking oral session at the 2022 European Society for Medical Oncology World Congress on Gastrointestinal Cancer (Abstract #LBA-1).
The company said the findings would be communicated with regulatory authorities in an effort to broaden the indications for tislelizumab provided it is authorized as a second-line treatment for recurrent locally advanced or metastatic oesophageal cancer. The FDA’s decision on the marketing application is expected by July 12. If tislelizumab is approved in the first-line oesophageal cancer therapy, it will compete with Bristol-Myers Squibb’s Opdivo (nivolumab), which was approved by the FDA in May, and Merck & Co’s Keytruda, which has been approved for these patients since 2021.
The drug is also being evaluated in Europe as second-line therapy for oesophageal cancer and NSCLC, as well as first-line therapy for advanced or metastatic NSCLC, and it is being evaluated in trials for small cell lung, gastric, liver cancers, bladder as well as nasopharyngeal carcinoma.
Janssen Announces U.S. FDA Breakthrough Therapy Designation Granted for Talquetamab for the Treatment of Relapsed or Refractory Multiple Myeloma
Janssen has announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) to its therapy talquetamab for the treatment of adult patients with relapsed or refractory multiple myeloma. The therapy is intended for patients who have previously received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.
Talquetamab is an investigational, off-the-shelf, T-cell redirecting bispecific antibody targeting both GPRC5D, a novel drug target, on multiple myeloma cells and CD3 on T-cells. The result from the Phase 1/2 “MonumenTAL-1” study data has formed the basis for the BTD. In June 2022, Janssen presented the data from the MonumenTAL-1 study at the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting.
Earlier in January 2021, European Medicines Agency (EMA) granted PRIME (PRIority MEdicines) designation, and in May 2021, the FDA granted the Orphan Drug Designation (ODD) to talquetamab
Multiple myeloma is incurable chronic blood cancer, affecting the white blood cells called plasma cells, and can be fatal. As per DelveInsight, in 2020, the total incident case of Multiple Myeloma was 91,693 in the 8MM. Among the 8MM, with 32,270 cases, the United States accounted for the highest number of cases, which are expected to rise by 2030. Several treatment options, including stem cell transplant, chemotherapy, targeted therapy, corticosteroids, proteasome inhibitors, immunomodulators, monoclonal antibodies, surgery, and radiation therapy, are available in the market for patients affected with relapsed or refractory multiple myeloma. However, there is a significant unmet need for new targets and treatments owing to the heterogeneity of the disease.
Bayer’s Kerendia Approves in China for Chronic Kidney Disease
In one of the major breakthrough approvals, Bayer’s Kerendia has received a green signal from the National Medical Products Administration (NMPA) China for the treatment of adults with chronic kidney disease associated with type 2 diabetes. Kerendia reduces the risk of sustained eGFR decline and end-stage kidney disease. The approval is expected to provide a big boost to Bayer in terms of the market potential in the chronic kidney disease (CKD) therapeutics domain. With the
NMPA approved Kerendia, based on the pivotal Phase III FIDELIO-DKD study result. The trial result was presented at the American Society of Nephrology’s (ASN) Kidney Week 2020. Kerendia (finerenone) is a non-steroidal, selective mineralocorticoid receptor (MR) antagonist. In the FIDELIO-DKD study, Kerendia was shown to reduce the risk of kidney disease progression or renal death by 18% when added to the highest tolerated dose of standard therapy. The therapy is also effective in lowering cardiovascular disease development, including death, nonfatal stroke, or hospitalization for heart failure.
China has the highest burden of diabetes-related chronic kidney disease worldwide and is one of the major health concerns in the country. China is among the major markets for Bayer to achieve its plan to successfully drive €1 billion-plus drug revenue from Kerendia. It is estimated that nearly 140 million people live with diabetes in China, plus a further 73 million undiagnosed cases. The launch of the therapy is expected to significantly improve the country’s chronic kidney disease treatment scenario.
FDA Puts Clinical Hold on Sanofi’s BTK Drug Tolebrutinib
The US FDA recently put a partial clinical hold on Phase 3 clinical trial studies of tolebrutinib for multiple sclerosis treatment and myasthenia gravis treatment. The drug was under clinical investigation by drug giant Sanofi where a limited number of drug-induced liver injury cases have been identified with tolebrutinib exposure in Phase 3 studies. The US drug regulatory paused this clinical trail leading to the participants who underwent the trial for less than 60 days shall suspend the usage of study drug. But more importantly, the participants who were taking the drug for more than 60 days should continue using the treatment.
The maximum number of patients impacted were determined to have concurrent complications known historically to predispose to drug-induced liver injury. Importantly, the elevations of laboratory values used for monitoring liver injury were considered to be reversible after drug discontinuation for all cases. After an earlier dialog with FDA about these cases, revision of study protocols was done in May 2022 to update the monitoring frequency, and also revision of enrollment criteria was done to exclude preexisting risk factors for hepatic dysfunction.
Enrollment in the clinical program continues with the revised study protocols and enhanced safety monitoring in countries outside of the U.S. Sanofi was working in proximity with the independent data monitoring committee members and investigators worldwide to evaluate the safety and effectiveness.
This clinical trial study for the multiple sclerosis treatment was initiated in the year 2019 and has been enrolling almost 2000 patients on tolebrutinib therapy with treatmentduration for almost 3 years. Sanofi is still thoughtful about the positive outcomes for the future of tolebrutinib as a highly capable oral treatment therapy for people living experiencing multiple sclerosis.
FDA Rejects Spero’s Tebipenem for Urinary Tract Infection
The US FDA gave a red flag to Spero Therapeutics application for complicated UTIs investigational treatment. Spero Therapeutics stated that it received a complete response letter from the drug regulatory indicating that the administration will not approve the oral administration of tebipenem pivoxil hydrobromide (tebipenem HBr) as the company’s Phase 3 study results evaluating the drug “was insufficient to support approval” for complicated urinary tract infections (cUTIs) and also suggested that additional clinical trail information will be required.
“We continue to believe that tebipenem HBr offers patients and their providers an important new treatment option, that if approved, has the potential to address the critical unmet need for a new oral antibiotic for patients with cUTI,” Ankit Mahadevia, MD, chief executive officer of Spero Therapeutics, said in the release. Mahadevia also said that Spero is “disappointed with the FDA’s decision” but will continue to move forward to address the FDA’s concerns and outline “a clear path forward for tebipenem HBr.” The release also states that Spero will “promptly request a Type A meeting with the FDA to gain further insights as to the pathway forward towards a potential regulatory approval for tebipenem HBr.”
Mahadevia also stated the company’s commitment in developing medications for unmet needs, such as cUTI and other diseases as well. He said tebipenem HBr remains an important part of Spero’s pipeline, along with SPR720 and SPR206, which are being developed for a rare, orphan pulmonary disease and multidrug-resistant Gram-negative infections in the hospital setting.
