FDA Approves Gilead Sciences’ Sunlenca
Sunlenca, a Gilead Sciences therapy for people with multidrug-resistant (MDR) HIV infection that only needs to be taken twice a year, has received FDA approval for the second time of asking. Sunlenca, which is based on the HIV capsid inhibitor lenacapavir, is intended to be used in addition to current HIV treatment. In trials, 81% of participants on the regimen achieved HIV RNA suppression, meaning their HIV levels were low enough to be considered undetectable after 6 months, with 83% showing continued viral load suppression after a year.
The drug was rejected by the US regulator earlier this year, just a few months after the program was put on hold due to manufacturing concerns, specifically the possibility of sub-visible particulate contamination from the borosilicate glass vials were originally used to produce the drug. After the clinical hold was lifted, Gilead switched to an aluminosilicate glass vial and refiled the drug in June. It also received EU approval for Sunlenca in August, making it a new option for patients who are unable to control their HIV with standard antiretroviral therapy (ART).
“This news is an important milestone in the work to help end the HIV epidemic as Sunlenca is now the only FDA-approved twice-yearly treatment for people with multi-drug resistant HIV,” said Daniel O’Day, Chairman and Chief Executive Officer, Gilead Sciences. “Gilead scientists have developed a unique and potent antiretroviral medicine in Sunlenca with the potential for flexible dosing options. Our goal is to deliver multiple long-acting options for treatment and prevention that are tailored to the needs of people living with HIV and people who could benefit from PrEP medicines.”
Gilead also plans to use lenacapavir in more and larger patient populations, including the general HIV-positive population, and for pre-exposure prophylaxis (PrEP) among people who have sex with HIV-positive partners.
FDA Gives Green Light to Roche’s CD20xCD3 Bispecific Antibody Lunsumio
The FDA has approved Roche’s CD20xCD3 bispecific antibody Lunsumio as a treatment for relapsed or refractory follicular lymphoma, following the European Commission’s approval in June. Lunsumio (mosunetuzumab) has been approved by the FDA for the same indication – patients who have previously received two or more lines of systemic therapy – making it the first CD20xCD3 bispecific to be approved for this type of non-Hodgkin lymphoma (NHL).
Lunsumio is a ready-to-use alternative to CAR-T therapies such as Gilead Sciences’ Yescarta (axicabtagene ciloleucel) and Novartis’ Kymriah (tisagenlecleucel), which have lengthy and complex manufacturing and administration procedures and necessitate in-hospital care.
Lunsumio could be administered as an outpatient therapy, eliminating the need for patients to wait for treatment and avoiding the lymphodepleting chemotherapy required to prepare the bone marrow to accept CAR-T cells. This makes the drug an option for patients who are too frail to undergo chemotherapy, but Roche believes it will be used more widely because its efficacy is comparable to that of CAR-Ts. Some analysts predict peak sales of USD 2 billion or more.
Lunsumio demonstrated an 80% overall response rate in patients who received at least two prior therapies in the pivotal phase II GO29781 study, with 60% going into complete remission from cancer. That is comparable to the rates seen in these patients with Kymriah and Yescarta, with the usual caveats about drawing comparisons between studies with different designs and protocols.
The approval is also good news for Biogen, which exercised an option on Lunsumio earlier this year, paying Roche’s Genentech unit USD 30 million upfront to share in any operating profits generated in the US in the low to mid 30% range, with royalties in the low single digits on sales elsewhere.
Meanwhile, Roche is conducting phase III studies to expand the indications for Lunsumio to maintain its lead over competing for CD20xCD3 bispecifics in trials, most notably Regeneron’s odronextamab, which produced encouraging results at this year’s ASH conference. The CELESTIMO trial is testing the drug in combination with lenalidomide in second-line FL, while SUNMO is testing Lunsumio in combination with Roche’s antibody-drug conjugate Polivy (polatuzumab vedotin) as a second-line or later therapy for diffuse large B-cell lymphoma (DLBCL), another type of NHL treated with CAR-T therapy.
EU Approves AstraZeneca’s Imfinzi Plus Chemo for Advanced Biliary Tract Cancer
On 21 December 2022, AstraZeneca updated that its therapy Imfinzi (durvalumab) has been approved in the European Union (EU) for the 1st-line treatment of adult patients with unresectable or metastatic Biliary Tract Cancer (BTC) in combination with chemotherapy (gemcitabine plus cisplatin). The approval follows the recommendation by The Committee for Medicinal Products for Human Use of the European Medicines Agency in November 2022.
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses. At the interim analysis, Imfinzi plus chemotherapy reduced the risk of death by 20% versus chemotherapy alone. Updated results from TOPAZ-1 after an additional 6.5 months of follow-up showed a 24% reduction in the risk of death versus chemotherapy alone, with more than two times as many patients treated with Imfinzi plus chemotherapy estimated to be alive at two years versus chemotherapy alone (23.6% versus 11.5%).
The approval of Imfinzi (durvalumab) was based on the primary results from the TOPAZ-1 Phase III trial published in the New England Journal of Medicine Evidence, and on the updated results presented at the European Society for Medical Oncology Congress 2022. TOPAZ-1 was a randomised, double-blind, placebo-controlled, multicentre, global Phase III trial of Imfinzi in combination with chemotherapy (gemcitabine plus cisplatin) versus placebo in combination with chemotherapy as a 1st-line treatment in 685 patients with unresectable advanced or metastatic Biliary Tract Cancer including intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer.
The primary endpoint was overall survival, and key secondary endpoints included progression-free survival, objective response rate, and safety. The trial was conducted in 105 centers across 17 countries, including the US, Europe, South America, and several countries in Asia, including South Korea, Thailand, Japan, and China. As per DelveInsight’s assessment, in the year 2021, the total incident cases of Biliary Tract Cancers was found to be 37,451 in the 7MM (i.e. the United Stats, EU5, and Japan).
Pfizer Files Blockbuster Hope Etrasimod for Ulcerative Colitis
On December 21, 2022, Pfizer announced that the U.S. Food and Drug Administration (FDA) has accepted for review a New Drug Application (NDA) for etrasimod for individuals living with moderately-to-severely active Ulcerative Colitis (UC). The FDA’s decision is expected in the second half of 2023. Moreover, the Marketing Authorization Application (MAA) for etrasimod in the same patient population has also been approved by the European Medicines Agency (EMA), and a decision is expected in the first half of 2024. Pfizer’s Etrasimod is an oral, once daily, selective sphingosine-1-phosphate (S1P) receptor modulator designed for optimized pharmacology and engagement of S1P receptors 1, 4, and 5. In addition to UC, it is being investigated for various immuno-inflammatory diseases.
These submissions were based on previously disclosed findings from the ELEVATE UC Phase 3 registrational programme (ELEVATE UC 52 and ELEVATE UC 12), which examined the safety and effectiveness of etrasimod 2 mg once daily in achieving clinical remission in UC patients who had previously failed or were intolerable to at least one conventional, biologic, or Janus kinase (JAK) inhibitor therapy. The primary and secondary objectives were met in both randomized, double-blind, placebo-controlled studies, and the safety profile was consistent with earlier research. Nearly two-thirds of patients in ELEVATE UC 52 and ELEVATE UC 12, respectively, were naïve to biologic or JAK inhibitor therapy.
Ulcerative Colitis is a chronic and often debilitating condition that affects an estimated 3.8 million people in North America and Europe. As per DelveInsight’s assessment, in 2021, the overall prevalent cases of Ulcerative Colitis were accessed to be around 2,221,000+ in the 7MM, which is expected to grow by 2032. Moreover, in the United States, the total number of prevalent cases of Ulcerative Colitis was around 1,017,000+ in the year 2021, which is expected to grow during the study period. Currently, the Ulcerative Colitis therapeutics market lacks advanced therapeutic options that are oral, effective, and have a favorable risk-benefit profile. The approval and the launch of Etrasimod are anticipated to improve the Ulcerative Colitis treatment scenario in the coming years.
FDA Approves Mosunetuzumab for Relapsed/Refractory Follicular Lymphoma
The Food and Drug Administration granted accelerated approval to mosunetuzumab-axgb, a bispecific CD20-directed CD3 T-cell engager for adult patients suffering with relapsed/refractory follicular lymphoma after two or more lines of systemic therapy.
Mosunetuzumab-axgb was evaluated in GO29781, an open-label, multicenter, multicohort study. The efficacy population consisted of around 90 patients suffering with relapsed or refractory follicular lymphoma who had received at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent.
The primary efficacy outcome measure was the objective response rate analysed by an independent review facility according to standard criteria for non-hodgkin’s lymphoma. The objective response rate was 80%, with 60% achieving complete responses. With a follow-up of 14.9 months among responders, the estimated median duration of response was 22.8 months, and the estimated duration of response rate at 12 months and 18 months was 62% and 57% respectively.
The prescribing information has a Boxed Warning for severe or life-threatening cytokine release syndrome. Warnings include infections, tumor flare, neurologic toxicity, and cytopenias. Among 218 patients having hematologic malignancies who received mosunetuzumab-axgb at the recommended dose, cytokine release syndrome occurred in 39% of patients, severe infections in 17%, tumor flare in 4%, and neurologic toxicity in 39%.
In the safety pool population of 218 patients, the most common adverse reactions were cytokine release syndrome, headache, fatigue, pyrexia, rash. The most common Grade III to IV laboratory abnormalities were decreased phosphate, decreased lymphocyte count, increased glucose, decreased neutrophil count, increased uric acid, white blood cell count, decreased hemoglobin and platelets.
FDA Grants Breakthrough Therapy Designation to Adagrasib Plus Cetuximab for KRAS G12C–Mutated Advanced CRC
Mirati Therapeutics declared that the FDA had granted breakthrough therapy designation to adagrasib in combination with cetuximab in patients suffering with KRASG12C-mutated, advanced colorectal cancer whose cancer has progressed following prior treatment with chemotherapy and anti-VEGF therapy. This designation is supported by results from the Phase 1b cohort of the KRYSTAL-1 trial.
The FDA program allows breakthrough therapy designation to expedite the development and regulatory review of drugs that have shown preliminary clinical evidence of a substantial improvement over available therapy in treating patients with severe diseases for atleast one clinically significant endpoint.
Additionally, the NEJM published findings from the ongoing multicohort KRYSTAL-1 Phase I/II study assessing adagrasib as monotherapy or combined with cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. These data reported promising clinical activity and shown a favorable tolerability profile with reversible adverse events.
Clinical Results Summary
- Out of 28 evaluable patients, the combination of adagrasib and cetuximab showed an objective response rate of 46%; a median duration of response of 7.6 months and a median PFS of 6.9 months.
- The safety profile of adagrasib was consistent with previously reported safety findings, and the safety of the combination of adagrasib and cetuximab did not result in synergistic adverse events. Grade III or IV treatment-related adverse events occurred in 34% of patients who received adagrasib monotherapy and 16% who received adagrasib and cetuximab in combination. No grade V TRAEs were observed.
A Phase III trial evaluating adagrasib in combination with cetuximab in patients suffering with KRASG12C-mutated colorectal cancer in the second-line setting compared with standard chemotherapy is currently ongoing.