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Insights+: Breakthrough Therapy Designation by the US FDA in 2020

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Insights+: Breakthrough Therapy Designation by the US FDA in 2020

Vartika Singh

Insights+: Breakthrough Therapy Designation by the US FDA in 2020

  • Breakthrough Therapy (BT) Designation is an expedited review program introduced in Section 902 of the Food and Drug Safety and Innovation Act of 2012
  • The Breakthrough Designation is granted to the drug candidates as monotherapy or in combination with other drugs intended to treat serious or life-threatening diseases and has shown substantial improvement over available therapies for the disease
  • PharmaShots has compiled a list of 41 therapies that have granted BTD by the US FDA in 2020

Aprea’s APR-246 Received the US FDA’s Breakthrough Therapy Designation for Myelodysplastic Syndromes with a TP53 Mutation

Date: Jan 30, 2020

Product: APR-246

  • The US FDA has granted BTD for APR-246 in combination with azacitidine to treat myelodysplastic syndromes (MDS) with a susceptible TP53 mutation
  • The BTD supports the development program for APR-246. The company continued its interaction with FDA regarding ongoing P-III study and clinical development program to advance APR-246
  • APR-246 is a small molecule that has demonstrated reactivation of mutant and inactivated p53 protein by restoring wild-type p53 conformation and function and thereby inducing programmed cell death in human cancer cells

Resverlogix Received the US FDA Breakthrough Therapy Designation for Apabetalone

Date: Feb 03, 2020

Product: Apabetalone

  • The US FDA has granted BTD for apabetalone in combination with SOC including high-intensity statins, for the secondary prevention of MACE in patients with T2D Mellitus and recent acute coronary syndrome
  • In 2019, Resverlogix reported results of P-III BETonMACE that showed a reduction in hospitalizations due to CHF as well as improving CV outcomes in two pre-specified subpopulations including those with CKD
  • Apabetalone is a first-in-class, BET inhibitor selective for the second bromodomain (BD2) within the BET proteins

Astellas and Seattle Genetics’ Padcev (enfortumab vedotin-ejfv) + Keytruda Received FDA’s Breakthrough Therapy Designation as 1L Treatment for Advanced Bladder Cancer

Date: Feb 20, 2020

Product: Padcev + Keytruda

  • The BT designation is based on P-Ib/II EV-103 study assessing Padcev + Keytruda (pembrolizumab) in patients with LA/ mUC who are unable to receive cisplatin-based CT treated in the 1L setting
  • The FDA’s BT designation expedite the development and review of drugs that are intended to treat a serious or life-threatening condition
  • Padcev is an ADC targeting Nectin 4 and has received the US FDA’s approval in Dec’2019, indicated for LA/mUC in patients prior treated with PD-1/PD-L1 and platinum-containing CT before & after surgery

ContraFect’s Exebacase Received the US FDA’s Breakthrough Therapy Designation for MRSA Bacteremia including Right-Sided Endocarditis

Date: Feb 24, 2020

Product: Exebacase

  • The BTD is based on P-II superiority trial assessing Exebacase + SOC antibiotic therapy vs SOC alone in patients with Staphylococcus aureus bacteremia, including endocarditis
  • In a pre-specified analysis of the subgroup with MRSA infections, the clinical responder rate @day14 (74.1% vs 31.3%). The Exebacase demonstrated a reduction in the 30-day all-cause mortality, 4days reduction in length of hospital stay, and reductions in 30-day hospital readmission rates in MRSA-infected patients
  • Exebacase is a recombinantly-produced lysin (cell wall hydrolase enzyme) with potent bactericidal activity against Staph aureus

Debiopharm’s Debio 1143 Received the US FDA’s Breakthrough Therapy Designation for Front-Line Treatment of Head and Neck Cancer

Date: Feb 27, 2020

Product: Debio 1143

  • The BTD is based on P-II results that demonstrated improvement of the 1EPs locoregional control rate @18mos. after CRT (21% improvement vs. control arm) and a marked PFS benefit vs the CRT + PBO arm after a 2-year follow-up period
  • The BTD reaffirms that Debio 1143 has the potential to offer benefit over the current SOC in LA-SCCHN, responding to the high unmet need in this debilitating cancer type
  • Debio 1143 is a potential first-in-class oral antagonist of IAPs, sensitizes tumor cells to radio-CT by promoting programmed cell death and fostering anti-tumor immunity

Genentech’s Esbriet (pirfenidone) Received FDA’s Breakthrough Therapy Designation for Unclassifiable Interstitial Lung Disease

Date: Mar 03, 2020

Product: Esbriet (pirfenidone)

  • The US FDA’s BT designation is based on P-II study assessing Esbriet vs PBO in patients aged =18-85yrs. with progressive fibrosing uILD, an FVC of =45%, DLco of =30%, >10% fibrosis on high-resolution CT and a high-resolution CT from the previous 12mos.
  • The P-II study results: slowed disease progression; predicted median change in FVC measured by home spirometry (-87.7 vs -157.1 ml) @24wks.; DLco and 6MWD trended in favor of Esbriet; safety & tolerability profile is comparable with P-III studies in IPF
  • Esbriet is an oral therapy, indicated to treat IPF and has received EMA & the FDA’s approval for the treatment of mild to moderate IPF in 2011 & 2014 respectively

Janssen’s JNJ-6372 Received the US FDA’s Breakthrough Therapy Designation for Non-Small Cell Lung Cancer

Date: Mar 11, 2020

Product: JNJ-6372

  • The FDA’s BT designation is based on a P-I study assessing the safety, efficacy & PK of JNJ-6372 as monothx. or in combination with lazertinib in patients with advanced NSCLC with EGFR Exon 20 insertion mutations, having disease progression on or after platinum-based CT
  • The study aims to determine the recommended P-II dose in patients with advanced NSCLC. The enrollment of patients is ongoing into part 2 dose expansion cohorts to assess JNJ-6372 as monothx. in multiple NSCLC sub-populations with genomic alteration
  • JNJ-6372 is an EGFR-MET bispecific Ab that targets activating and resistant EGFR and MET mutations and amplifications. The development of Ab followed the Janssen’s licensing agreement with Genmab for its DuoBody technology platform

Eli Lilly and Incyte’s Olumiant (baricitinib) Received the US FDA’s Breakthrough Therapy Designation for Alopecia Areata

Date: Mar 16, 2020

Product: Olumiant (baricitinib)

  • The FDA’s BT designation is based on P-II results of P-II/III BRAVE-AA1 study assessing baricitinib vs PBO in patients with AA
  • The P-II portion of the BRAVE-AA1 study demonstrated no new safety signals with no SAEs @36wks. Additionally, P-III portion of BRAVE-AA1 & P-III BRAVE-AA2 study, are currently evaluating baricitinib (2mg/4mg) vs PBO in patients with AA
  • Olumiant is an approved treatment for adults with moderately to severely active RA, approved in ~65+ countries, including the US, member states of the EU and Japan

Acceleron’s Sotatercept Received the US FDA’s Breakthrough Therapy Designation for Pulmonary Arterial Hypertension

Date: Apr 08, 2020

Product: Sotatercept

  • The US FDA has granted BTD to sotatercept for the treatment of patients with pulmonary arterial hypertension (PAH)
  • Earlier, the company reported results of the P-II PULSAR study that demonstrated sotatercept has the potential to shift the current treatment paradigm and provide benefits to patients with PAH on top of currently available therapies
  • Sotatercept is an investigational agent designed to be a selective ligand trap for members of the TGF-beta superfamily to rebalance BMPR-II signaling

EMD Serono and Pfizer’s Bavencio (avelumab) Received the US FDA’s Breakthrough Therapy Designation as 1L Maintenance Treatment of Locally Advanced or Metastatic Urothelial Carcinoma

Date: Apr 09, 2020

Product: Bavencio (avelumab)

  • The companies have completed the submission of sBLA to the US FDA as 1L maintenance therapy for patients with LA/m-UC and have received FDA’s BT designation for the same indication. The sBLA is being reviewed under the FDA’s RTOR pilot program
  • The sBLA is based on P-III JAVELIN Bladder 100 study assessing Bavencio + BSC vs BSC as monothx. in 700 patients with UC with no disease progression after platinum-based induction CT
  • The study resulted in meeting 1EPs of OS in each of the co-primary populations of all randomized patients and patients with PD-L1-positive tumors. Bavencio is a PD-L1 antibody, acts by blocking the interaction of PD-L1 with PD-1 receptors

Takeda’s Mobocertinib (TAK-788) Received the US FDA’s Breakthrough Therapy Designation for NSCLC Patients with EGFR Exon 20 Insertion Mutations

Date: Apr 28, 2020

Product: Mobocertinib (TAK-788)

  • The BT designation is based on P-I/II study assessing the safety and efficacy of mobocertinib (160mg, qd) in patients with LA/ m NSCLC, harboring EGFR exon 20 insertion mutations, prior treated with systemic CT
  • The P-I/II ongoing study results: mPFS (7.3mos.); ORR (43%); safety profile was manageable. The mobocertinib development program began in the NSCLC population and is expected to expand to additional underserved populations in other tumor types
  • Mobocertinib is a potent, small-molecule TKI, designed to selectively target EGFR and HER2 exon 20 insertion mutations and has received the US FDA’s ODD in 2019

Daiichi Sankyo and AstraZeneca’s Enhertu (fam-trastuzumab deruxtecan-nxki) Received the US FDA’s Breakthrough Therapy Designation for HER2 Mutant Metastatic Non-Small Cell Lung Cancer

Date: May 18, 2020

Product: Enhertu (fam-trastuzumab deruxtecan-nxki)

  • The US FDA’s BT designation is based on an ongoing P-II DESTINY-Lung01 study assessing Enhertu in 170 patients with HER2 mutant or HER2 overexpressing unresectable and m-nsq. NSCLC, progressed after one or more systemic therapies including CT, molecular targeted therapy or immunotherapy and data from P-I study, published in Cancer Discovery
  • The overall safety and tolerability profile of Enhertu in the ongoing DESTINY-Lung01 study is consistent with the P-I study. This designation marks the third BT designation for Enhertu in the US and the fourth expedited regulatory designation received globally
  • Enhertu is a HER2 directed ADC, received accelerated approval in the US & approval in Japan under the conditional early approval system for unresectable/ metastatic HER2 positive metastatic BC, prior treated with anti-HER2 based regimens

Insmed’s Brensocatib Received the US FDA’s Breakthrough Therapy Designation to Treat Non-Cystic Fibrosis Bronchiectasis

Date: Jun 08, 2020

Product: Brensocatib

  • The BTD is based on P-II WILLOW study assessing brensocatib vs PBO in adults with NCFBE for reducing exacerbations
  • Insmed expects to initiate a P-III program for brensocatib in bronchiectasis in the H2’21
  • Brensocatib is a novel oral, reversible DPP1 inhibitor, currently being developed for the treatment of bronchiectasis and other inflammatory diseases

 Axsome’s AXS-05 Received the US FDA’s Breakthrough Therapy Designation for the Treatment of Alzheimer’s Disease Agitation

Date: Jun 26, 2020

Product: AXS-05

  • The US FDA has granted the BTD for AXS-05 to treat AD agitation. The designation offers potential for expedited development and review
  • The designation was based on P-II/III ADVANCE-1 study assessing AXS-05, bupropion vs PBO in 366 patients with AD. The study demonstrated substantial improvement in agitation; mean reduction from baseline in the CMAI total score @5wks. (15.4 vs 11.5 points); superior to bupropion on the CMAI total score and was well tolerated
  • AXS-05 is a novel, oral, investigational NMDA receptor antagonist with multimodal activity has now received two BTD for separate CNS indications

Telix Received the US FDA’s Breakthrough Therapy Designation for TLX250-CDx (89Zr-girentuximab)

Date: Jul 01, 2020

Product: TLX250-CDx (89Zr-girentuximab)

  • The US FDA has granted BTD for Telix’s renal cancer imaging product TLX250-CDx (89Zr-girentuximab)
  • Under BTD, the FDA will work closely with Telix to provide guidance on the development of TLX250-CDx for the diagnosis of “indeterminate renal masses” that have been identified on CT or MRI imaging
  • TLX250-CDx is being developed for the purpose of determining “indeterminate renal masses” are either ccRCC or non-ccRCC, using PET imaging

EspeRare’s ER-004 Received the US FDA’s Breakthrough Therapy Designation for Prenatal Treatment of XLHED

Date: Jul 06, 2020

Product: ER-004

  • The BT designation is provided on three results from three XLHED subjects with a course of ER-004 intra-amniotic injections during the third trimester of pregnancy while the results were published in NEJM and showed profound and life-changing effects on infants
  • The US FDA’s BT designation is granted to expedite the development and review of drugs for serious or life-threatening conditions allowing the program to benefit from all the FDA’s fast-track program feature
  • In H2’21, EspeRare to enroll patients for the study which is also benefited with Fast Track and ODD and has also received the EMA’s PRIME designation and ODD

Concert’s CTP-543 Received the US FDA’s Breakthrough Therapy Designation to Treat Alopecia Areata

Date: Jul 08, 2020

Product: CTP-543

  • The BTD is based on a P-II study assessing CTP-543 (4/8/12mg, bid) vs PBO in 149 patients with moderate-to-severe alopecia areata
  • Results: 8 & 12mg doses of CTP-543 met its 1EPs with differences in the percentage of patients achieving a = 50% relative change from baseline @24wks. as measured by SALT. Therapy was well-tolerated and showed significant hair regrowth
  • CTP-543 is a JAK1 & JAK2 inhibitor and has received the US FDA’s FTD for AA. The company plans to initiate a P-III study in Q4’20

Roche’s Mosunetuzumab Received the US FDA’s Breakthrough Therapy Designation to Treat Relapsed or Refractory Follicular Lymphoma

Date: Jul 14, 2020

Product: Mosunetuzumab

  • The US FDA has granted BTD to the Roche’s mosunetuzumab for the treatment of adult patients with r/r FL, prior treated with at least two systemic therapies
  • The BT designation is based on P-I/Ib GO29781 study assessing mosunetuzumab in R/R non-Hodgkin lymphoma. The safety profile of the therapy was consistent with its mechanism of action
  • Mosunetuzumab is an investigational CD20xCD3 T-cell engaging bispecific that targets CD20 on the surface of B-cells and CD3 on the surface of T-cells, being evaluated in clinical development program across several lymphoma indications both as monothx. and combination therapy

MyoKardia’s Mavacamten Received the US FDA’s Breakthrough Therapy Designation for Symptomatic Patients with Obstructive Hypertrophic Cardiomyopathy

Date: Jul 23, 2020            

Product: Mavacamten

  • The US FDA has granted BTD to mavacamten for the treatment of symptomatic, obstructive hypertrophic cardiomyopathy (HCM)
  • In May’2021, MyoKardia reported the results of the P-III EXPLORER study that demonstrated the robust treatment effect, with patient responses to treatment, including reductions in symptoms, improvements in cardiac function and reduction or elimination of the obstruction of the left ventricle and was well tolerated
  • MyoKardia is currently preparing an NDA for mavacamten, with plans to submit to the FDA in Q1’21

Merck’s MK-6482 Received the US FDA’s Breakthrough Therapy Designation to Treat Patients With Von Hippel-Lindau Disease-Associated Renal Cell Carcinoma

Date: Jul 29, 2020

Product: MK-6482

  • The designation is based on P-II study evaluating MK-6482 in patients with VHL-associated RCC with nonmetastatic RCC tumors >3cms in size, unless immediate surgery is required
  • The FDA’s BT designation is granted to expedite the development and review of medicines that are intended to treat serious or life-threatening conditions and have demonstrated preliminary clinical evidence indicating that the medicine may provide a substantial improvement over available therapy on at least one clinically significant endpoint
  • MK-6482 (formerly PT2977) is an investigational oral HIF-2a inhibitor, currently being evaluated in a P-III trial in advanced RCC (NCT04195750), a P-II trial in VHL-associated RCC (NCT03401788), and a P-I/II dose-escalation and dose-expansion trial in advanced solid tumors, including advanced RCC (NCT02974738)

AstraZeneca’s Tagrisso (osimertinib) Received the US FDA’s BT Designation for the Adjuvant Treatment of Patients with Stage IB-IIIA EGFR-Mutated Lung Cancer

Date: Jul 30, 2020

Product: Tagrisso (osimertinib)

  • The BT designation is based on P-III ADAURA trial which involves assessing Tagrisso (80 mg) vs PBO in 682 patients with Stage IB, II, IIIA EGFRm NSCLC following complete tumor resection and adjuvant chemotherapy as indicated across 20 centers and 200+ countries including the US, EU, South America, Asia, and the Middle East
  • The study resulted in improvement in DFS, reduction in risk of disease recurrence, or death by 79% in the adjuvant treatment of Stage IB-IIIA EGFRm NSCLC patients, also presented at ASCO 2020. Additionally, the trial will continue to assess OS
  • Tagrisso (osimertinib) is third-generation, irreversible EGFR-TKI once-daily oral tablets approved 1st-line EGFRm advanced NSCLC and EGFR T790M mutation-positive advanced NSCLC in the US, Japan, China, the EU

Takeda’s Pevonedistat Received the US FDA’s Breakthrough Therapy Designation to Treat Patients with Higher-Risk Myelodysplastic Syndrome

Date: Jul 31, 2020

Product: Pevonedistat

  • The BT designation is based on the final analysis of the Pevonedistat-2001 P-II study assessing pevonedistat + azacitidine vs azacitidine as monothx. in patients with rare leukemias, including HR-MDS
  • The 1EPs of the study include OS, EFS, CR and transfusion independence, and AE profile. The designation addresses the needs of people living with HR-MDS, for whom few therapies exist, and the benefits are limited
  • Pevonedistat is a first in class NEDD8-activating enzyme (NAE) inhibitor. The pre-clinical studies demonstrated the inhibition of NAE, blocked the modification of select proteins, which resulted in the disruption of cell cycle progression and cell survival, leading to cancer cell death

BeyondSpring’s Plinabulin Received the US FDA’s and NMPA’s Breakthrough Therapy Designations for Chemotherapy-Induced Neutropenia Indication

Date: Sep 08, 2020

Product: Plinabulin

  • The designation is based on P-III PROTECTIVE-2 evaluating Plinabulin + Neulasta vs Neulasta alone for the treatment of CIN
  • In the protocol-specified interim analysis, combination regimen was better than Neulasta alone in achieving the 1EPs with p<0.01 and have a well-tolerated safety profile with fewer Grade 4 AEs
  • The company plans to report full results of the P-III PROTECTIVE-2 study in Q4’20 and file an NDA with the FDA by the end of 2020. The company has submitted an NDA to the NMPA on a rolling basis in Q1’20

Junshi’s Toripalimab Received the US FDA’s Breakthrough Therapy Designation for the Treatment of Nasopharyngeal Carcinoma

Date: Sept 10, 2020

Product: Toripalimab

  • The US FDA has granted the BTD for Toripalimab to treat nasopharyngeal carcinoma. The BTD will allow the company to work with the FDA to bring the therapy to patients worldwide expeditiously
  • The US FDA’s BTD for the therapy supports and accelerate the commercial development plan of Toripalimab in the US
  • Toripalimab is the 1st anti-PD-1 Ab to receive the BTD in China, it marks another regulatory milestone after FDA granted ODD in May’2020

Sanofi’s Dupixent Received the US FDA’s Breakthrough Therapy Designation for Eosinophilic Esophagitis

Date: Sept 14, 2020

Product: Dupixent

  • The BT designation is based on Part A of P-III study assessing Dupixent (300mg) in 81 patients aged =12yrs. with EoE for 24wks.
  • The Part A of P-III study met its co-1EPs and 2EPs i.e. reduction in symptoms, esophageal inflammation, abnormal endoscopic findings in the esophagus and has demonstrated safety results consistent with the known safety profile of Dupixent in its approved indications
  • The P-III study is ongoing with additional patients enrolling in Part B as well as patients continuing in a 28wks. extended active treatment period (Part C) after completing either Part A or B. Dupixent is the first and only biologic to show positive P-III results in patients aged =12yrs. with EoE and has received the US FDA’s ODD in 2017

Gilead’s Magrolimab Received the US FDA’s Breakthrough Therapy Designation for Myelodysplastic Syndrome

Date: Sept 16, 2020

Product: Magrolimab

  • The BT designation is based on part B of the P-I study assessing Magrolimab + Azacitidine in 33 previously untreated intermediate, high, and very high-risk MDS patients. The results are presented at the 2020 European Hematology Society Congress
  • The part B of the P-I study showed positive results with 91% achieving OR and 42% achieving CR and the combination was generally well-tolerated
  • Magrolimab is anti-CD47 mAb, currently being studied P-III ENHANCE trial in previously untreated higher MDS risk evaluating the safety and efficacy of dual regimen, as measured by CR and duration of CR. The therapy has received the US FDA’s FT designation for MDS, AM

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