HUTCHMED Completes Rolling Submission of NDA to FDA for Fruquintinib

HUTCHMED (China) Limited announced the completion of the rolling submission of a New Drug Application (“NDA”) to the United States Food and Drug Administration (“FDA”) for fruquintinib, its highly selective and potent oral inhibitor of VEGFR-1, -2, and -3, for the treatment of refractory metastatic colorectal cancer. 

“This FDA submission is a significant milestone for patients in the United States who have metastatic CRC, one of the most common and deadly cancers in the United States and around the world.” In China, where it has been available since 2018, fruquintinib is an important treatment option for patients with metastatic CRC. We are excited to collaborate with our partner Takeda to commercialize fruquintinib outside of China, and we remain on track to submit regulatory filings in Europe and Japan later this year,”

Dr. Michael Shi, HUTCHMED’s Head of R&D and Chief Medical Officer

The NDA is backed up by data from the global Phase III multi-regional clinical trial (“MRCT”) FRESCO-2 study, which was conducted in the United States, Europe, Japan, and Australia and compared fruquintinib plus best supportive care (“BSC”) vs. placebo plus BSC in patients with refractory metastatic CRC, as well as data from the FRESCO study in China. In 2023, a Marketing Authorization Application (MAA) will be submitted to the European Medicines Agency (EMA), and an NDA will be submitted to the Japan Pharmaceuticals and Medical Devices Agency (PMDA).

HUTCHMED and Takeda Pharmaceutical Company Limited signed an exclusive license agreement in March 2023 to advance the global development, commercialization, and manufacturing of fruquintinib outside of China. Frucquintinib is approved in China under the brand name ELUNATE® and is on the China National Reimbursement Drug List (“NRDL”). In collaboration with Eli Lilly and Company, HUTCHMED markets fruquintinib in China.

Cytokinetics to Discontinue ALS Drug Candidate Following Phase III Trial Failure

Cytokinetics, Incorporated announced that the Data Monitoring Committee (DMC) for COURAGE-ALS (Clinical Outcomes Using Reldesemtiv on ALSFRS-R in a Global Evaluation in ALS) recently convened to conduct the second planned interim analysis of this Phase III amyotrophic lateral sclerosis clinical trial.

The DMC reviewed unblinded data from COURAGE-ALS and recommended that the clinical trial be terminated due to futility because there was no evidence of effect in patients treated with reldesemtiv versus placebo on the primary endpoint of change from baseline to 24 weeks in ALSFRS-R or key secondary endpoints. Based on these findings, the COURAGE-ALS study will come to an end. Furthermore, Cytokinetics intends to discontinue treatment with reldesemtiv in all patients, including those enrolled in the open-label extension study, COURAGE-ALS OLE.

“We are extremely disappointed with this outcome and would like to thank people with ALS, carers, investigators, and clinical trial staff for participating in COURAGE-ALS. Cytokinetics has been committed to the ALS community for over a decade and recognizes the importance of bringing new potential medicines to the forefront for this terrible disease.” We will evaluate the next steps for our neuromuscular development programs in the coming months.”

Cytokinetics CEO and President Robert I. Blum.

The second interim analysis was initiated 24 weeks after at least one-third of the planned sample size in COURAGE-ALS was randomized. At the time of the interim analysis, approximately 460 patients had been randomized, with over 200 having completed the 24-week assessment of trial endpoints. This interim analysis assessed the primary and key secondary endpoints for potential futility and provided for a potential fixed increase in total enrollment if it had been deemed necessary to augment the trial’s statistical power or to continue the trial to its conclusion as planned. Cytokinetics intends to notify all regulatory agencies and COURAGE-ALS clinical trial investigators of these preliminary findings. The entire trial data set is being analyzed, and more information will be presented at an upcoming medical meeting.

FDA Approves Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma

Enfortumab vedotin-ejfv in combination with pembrolizumab has received accelerated approval from the Food and Drug Administration for treating patients with locally advanced or metastatic urothelial carcinoma who cannot receive cisplatin-containing chemotherapy.

Efficacy was evaluated in EV-103/KEYNOTE-869, a multi-cohort study. Both the dose escalation cohort and Cohort A were single-arm cohorts that administered enfortumab vedotin-ejfv and pembrolizumab to patients. In contrast, patients in Cohort K were randomized to either the combination or enfortumab vedotin-ejfv alone. Individuals who had not received any systemic therapy for locally advanced or metastatic disease were not qualified to undergo cisplatin-containing chemotherapy. A combined number of 121 patients were treated with enfortumab vedotin-ejfv and pembrolizumab.

Blinded independent central review using RECIST v1.1 was used to determine the objective response rate and duration of response as primary efficacy outcome measures. Among the 121 patients, the confirmed objective response rate was 68%, with 12% of them experiencing complete responses. The median duration of response for the dose escalation cohort + Cohort A was 22 months, whereas for Cohort K, it was not yet reached.

The adverse reactions, including laboratory abnormalities, that were observed in more than 20% of cases were increased glucose, increased aspartate aminotransferase, peripheral neuropathy, decreased lymphocytes, fatigue, rash, decreased hemoglobin, increased creatinine, increased alanine aminotransferase, reduced sodium, decreased appetite, nausea, dysgeusia, decreased potassium, decreased neutrophils, increased lipase, decreased albumin, alopecia, decreased phosphate, decreased weight, dry eye, dizziness, arthralgia, diarrhea, pruritus, urinary tract infection, constipation, potassium increased, calcium increased, peripheral edema, and dry skin.

Enfortumab vedotin-ejfv, when used in combination with pembrolizumab, should be administered intravenously at a dose of 1.25 mg/kg over 30 minutes on Days 1 and 8 of a 21-day cycle, until disease progression or unacceptable toxicity. Pembrolizumab, given on the same day after enfortumab vedotin, is recommended at a dose of 200 mg every three weeks or 400 mg every six weeks until disease progression, unacceptable toxicity, or up to 24 months.

To facilitate the FDA’s assessment, the applicant voluntarily submitted the Assessment Aid, which was used in this review. Additionally, this application was granted priority review and breakthrough designation, both of which are expedited programs outlined in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Nanoscope Gene Therapy Clears Phase II Retinitis Pigmentosa Trial

Nanoscope Therapeutics announced the top-line results of the RESTORE clinical trial, a Phase 2b multicenter, randomized, double-masked, sham-controlled study of MCO-010. This optogenetic therapy uses Multi-Characteristic Opsin and can restore vision in advanced retinitis pigmentosa patients, regardless of gene mutation, by being activated by ambient light. MCO-010 has received both orphan drug and fast-track designations from the U.S. Food and Drug Administration.

During the RESTORE trial, 18 patients with severe vision impairment due to retinitis pigmentosa were given a single intravitreal injection of MCO-010, while the remaining 9 received a sham intravitreal injection procedure. The results showed improvements in vision function following treatment with MCO-010, which were consistent with previous studies and had a favorable safety profile. The primary outcome measure was the change in the mean Multi-Luminance Y-Mobility Test score compared to the placebo group. Additionally, critical efficacy assessments included the Multi-Luminance Shape Discrimination Test and Best-Corrected Visual Acuity. A clinically meaningful change was defined as a two or more luminance level change for MLYMT and MLSDT. A negative change in BCVA, indicating improved visual acuity, was considered clinically significant if it was a 0.3 LogMAR change.

Key efficacy outcomes at 12 months were:

  • At the 12-month follow-up, 16 out of 18 (88.9%) patients treated with MCO-010 showed an improvement of two or more luminance levels in MLYMT or MLSDT, while only 4 out of 9 (44.4%) patients who received placebo showed similar improvement (with p-value < 0.05).
  • Out of the patients treated with MCO-010, 12 out of 18 (66.7%) showed improvement of two or more luminance levels in the MLYMT, while only 3 out of 9 (33.3%) receiving placebo had similar improvement.
  • Out of 18 patients who received MCO-010, 10 showed an improvement of two or more luminance levels in the MLSDT, whereas only 2 out of 9 patients who received a placebo showed a similar improvement.
  • Seven out of 18 patients treated with MCO-010 demonstrated an improvement of -0.3 LogMAR or more in BCVA compared to only one out of nine patients who received the placebo.
  • The difference between MCO-010 treatment and placebo in the primary outcome measure, which was the change in MLYMT score, was +1.0 (95%CI 0.0, 3.0).

Apart from demonstrating a clinically meaningful effect, MCO-010 showed good tolerance with no severe ocular or systemic adverse events observed, except for one SAE in a placebo-treated patient. The incidence of treatment-emergent adverse events was similar across study arms. The most commonly reported ocular TEAEs in both treatment arms were anterior chamber cells, ocular hypertension, and conjunctival hemorrhage.

The recently announced results of the RESTORE trial are consistent with the earlier Phase 1/2 study, showing a positive impact on visual function in the majority of MCO-010 treated patients and a safe profile. It is important to note that there are currently no available treatments to improve eyesight in people with RP who suffer from severe vision loss. The company anticipates presenting the RESTORE top-line outcomes at upcoming medical conferences.

Cabaletta Bio Receives FDA Clearance of IND Application for CABA-201 for Treatment of Systemic Lupus Erythematosus

On March 31, 2023, Cabaletta Bio, Inc. (Nasdaq: CABA) announced that the Company’s Investigational New Drug (IND) application for CABA-201, a 4-1BB-containing fully human CD19-CAR T cell investigational therapy, has been cleared by the U.S. Food and Drug Administration (FDA). The Company plans to initiate a Phase 1/2 clinical trial of CABA-201 for the treatment of systemic lupus erythematosus (SLE) in patients with active lupus nephritis (LN) or active SLE without renal involvement.

The Phase 1/2 clinical trial will begin in patients with either active LN or SLE without renal involvement. Based on its similarity to the product used in the Nature Medicine paper, we believe CABA-201 has the potential to provide deep and durable responses for patients with Systemic Lupus Erythematosus and possibly other autoimmune diseases where B cells play a role to initiate or sustain disease pathology. By achieving a timely IND clearance, we believe we are well positioned to generate 3-month clinical data on efficacy endpoints and tolerability for patients dosed with CABA-201 by the first half of 2024.”

Steven Nichtberger, M.D., Chief Executive Officer and Co-founder of Cabaletta

CABA-201 is designed to be given as a one-time infusion, with the potential to transiently but fully eliminate B cells, thus enabling an “immune system reset” and durable remission in patients with SLE. The Phase 1/2 clinical trial is an open-label dose evaluation study designed to evaluate CABA-201 in SLE subjects with active LN or active SLE without renal involvement. Subjects will be treated with a standard preconditioning regimen consisting of fludarabine and cyclophosphamide prior to CABA-201 infusion. This represents the first trial that employs Cabaletta’s CARTA (Chimeric Antigen Receptor T cells for Autoimmunity) strategy.

SLE is a chronic (long-term), potentially severe, autoimmune disease that causes systemic inflammation, which affects multiple organs. In addition, affecting the skin and joints, it can affect other organs in the body, such as the kidneys and the tissue lining. As per DelveInsight, the total prevalent population of Systemic Lupus Erythematosus in the seven major markets was 658,000+ in 2021, which is expected to rise during the forecast period (2022-2032). In the United States, the Systemic Lupus Erythematosus accounted for 355,000+ prevalent cases in 2021. In EU5 countries, the UK had the highest prevalence of Systemic Lupus Erythematosus patients, with 69,00+ cases. Moreover, in Japan, the prevalence of Systemic Lupus Erythematosus was 68,854 in 2021. It most commonly impacts young women between the ages of 15 and 40, with higher frequency and more severity in people of color, where the immune system attacks healthy tissue throughout the body.

Decibel Therapeutics Receives European Orphan Drug Designation for Lead Gene Therapy Candidate DB-OTO

On March 30, 2023, Decibel Therapeutics (Nasdaq: DBTX) announced that the European Medicines Agency (EMA) Committee on Orphan Medicinal Products (COMP) had issued a positive opinion on orphan drug designation for DB-OTO. DB-OTO is Decibel’s lead gene therapy product candidate developed with the aim to provide durable, high-quality, physiological hearing to individuals with profound, congenital hearing loss caused by mutations of the otoferlin gene. This opinion was adopted by the European Commission (EC). Decibel Therapeutics is working on DB-OTO in partnership with Regeneron Pharmaceuticals. 

“We are pleased to receive this important designation from the EC, which supports our conviction that innovative treatments for congenital hearing loss are urgently needed. Decibel has generated compelling preclinical data showing DB-OTO’s potential, and we are on track to initiate CHORD™, our global Phase 1/2 clinical trial of DB-OTO, in the first half of this year.”

Laurence Reid, Ph.D., Chief Executive Officer at Decibel

DB-OTO is an AAV dual vector gene therapy delivered via intracochlear injection. OTOF is a large protein expressed in cochlear inner hair cells that enables the communication between the sensory cells of the inner ear and the auditory nerve by regulating synaptic transmission. Earlier, DB-OTO received Orphan Drug and Rare Pediatric Disease designations from the U.S. Food and Drug Administration in 2021. Moreover, the US FDA has cleared the IND Application for DB-OTO for the Phase 1/2 clinical trial of DB-OTO in pediatric patients, expected in the first half of 2023. Currently, there are no approved pharmacologic treatment options for people with hearing loss caused by genetic mutations of otoferlin. The approval and the launch of DB-OTO is anticipated to immensely improve the treatment dynamics and the health outcome for the affected patients.