An Analysis of Drugs with FDA Granted Breakthrough Therapy Designations

Created in July 2012 by the U.S. Food and Drug Administration (FDA) as part of FDA Safety and Innovation Act (FADSIA), the breakthrough therapy designation is intended to speed up the development and review of drugs for serious or life-threatening illnesses. A company can request that FAD designate a drug a breakthrough therapy if early data from clinical trials shows that it may be a significant improvement over other drugs currently being used.

Though the FDA already has methods to expedite the development of some new drugs – including fast track designation, accelerated approval, and priority review – breakthrough therapy designation is different. It’s the only method specifically focused on a drug that treats serious or life-threatening conditions with preliminary clinical evidence indicating that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies.

As of February 7, 2014, FDA lists 141 total requests for Breakthrough designation, 37 requests granted, and 72 requests denied. FDA does not disclose information regarding specific drugs or sponsors. Currently, 32 granted requests have been publicly announced by their sponsors for compounds that treat a range of illnesses, including cancer, hepatitis C and cystic fibrosis.

Approved Drugs through the FDA’s Breakthrough Therapy Designations

Name

Indication

Company

Date
Disclosed

Date
Approved

Gazyva/
Obinutuzumab

Chronic
Lymphocytic Leukemia

Roche

May 15, 2013

Nov 1, 2013

Imbruvica/Ibrutinib

Mantle Cell
Lymphoma

Pharmacyclics/J&J

Feb 12, 2013

Nov 13, 2013

Sovaldi/Sofosbuvir

Hepatitis C

Gilead

July 25,
2013

Dec 6, 2013

Publicly disclosed drugs with breakthrough designations as of February 7, 2014 in order of their of announcement dates.

Drug

Indication

Targets

Sponsor

Current
Status

Date
Announced

Ivacaftor (Kalydeco)

Cystic
fibrosis

CFTR

Vertex

sNDA

1/6/2013

Ivacaftor +

Lumacaftor

Cystic
fibrosis

CFTR

Vertex

III

1/6/2013

Ibrutinib (Imbruvica)

Mantle cell lymphoma

BTK

Pharmacyclics / Johnson & Johnson

Approved

2/12/2013

Ibrutinib

Waldenstrom’s macroglobunaemia

BTK

Pharmacyclics / Johnson & Johnson

II/III

2/12/2013

LDK378

Non-small cell lung cancer

ALK

Novartis

III

3/15/2013

Ibrutinib

Chronic/small lymphocytic leukaemia

BTK

Pharmacyclics / Johnson & Johnson

II/III

4/8/2013

Palbociclib

Breast cancer

CDK4,CDK6

Pfizer

II/III

4/10/2013

Lambrolizumab

(MK-3475)

Advanced melanoma

PD1

Merck

III

4/24/2013

Daclatasvir +asunaprevir +

BMS-791325

Hepatitis C

NS5A,HS3,NS5B

Bristol-Myers
Squibb

III

4/25/2013

SD-101

Epidermolysis bullosa

undisclosed

Scioderm

IND

4/29/2013

Daratumumab

Multiple myeloma

CD38

Johnson
& Johnson/Genmab

II

5/1/2013

ABT-450 +

ABT-267 +

ABT-333

Hepatitis C

NS3/4A,NS5A,
NS5B

AbbVie

III

5/6/2013

Obinutuzumab (Gazyva)

Chronic lymphocytic leukaemia

CD20

Roche

Approved

5/15/2013

Sebelipase alfa

LAL deficiency

Recombinant
LAL enzyme

Synageva

III

5/20/2013

Asfotase alfa

hypophosphatasia

Recombinant
alkaline phosphatase

Alexion

II/III

5/28/2013

Serelaxin (RLX030)

Acute heart failure

Relaxin
family peptide receptors

Novartis

NDA/BLA

6/21/2013

Drisapersen

Duchenne muscular dystrophy

Dystrophin
gene

GlaxoSmithKline/Prosensa

III

6/27/2013

Sofosbuvir + Ledipasvir

Hepatitis C

NS5B,
NS5A

Gilead

III

7/25/2013

Bimagrumab

Sporadic inclusion body myositis

Activin
A

Novartis

II/III

8/20/2013

Amifampridine phosphate

Lambert–Eaton myasthenic syndrome

Potassium Channels

Catalyst Pharma

III

8/27/2013

Entinostat

Advanced breast cancer

HDAC

Syndax

II

9/11/2013

Ofatumumab

First Line CLL

CD20

GSK/Genmab

sNDA

9/13/2013

Volasertib

Acute Myeloid Leukemia

PLK1

Boehringer Ingelheim

III

9/17/2013

Alectinib

ALK-positive NSCLC

ALK

Roche

II

9/23/2013

MK‑5172 + MK‑8742

Hepatitic C

NS3/4A,
NS5A

Merck

II

10/22/2013

ALXN1101

Molybdenum cofactor deficiency type A

cPMP
replacement

Alexion

III

10/24/2013

Andexanet Alfa (PRT4445)

Anticoagulant

Factor
Xa

Portola

III

11/25/2013

Tafenoquine (他非诺喹)

P. vivax malaria

P. vivax  

GSK/MMV

II

12/20/2013

Tafinlar  (Dabrafenib)

NSCLC

BRAF

GSK

approved

1/13/2014

Idelalisib

CLL

PI3K

Gilead

NDA

1/13/2014

 

Kalydeco + VX-661

Cystic fibrosis(two copies of F508del mutation)

CTFR

Vertex

Phase II (2014)

Jan 29, 2014

Eltrombopag(Promacta, Revolade)

severe aplastic anaemia

c-mpl (TpoR)

GSK/Ligand

Approved

Feb 3, 2014

Kalydeco (Ivacaftor)

Indication: Cystic fibrosis
Company:Vertex Pharmaceuticals
Current stage: First approved on January 31st, 2012
Expected launch:2014
Date announced for breakthrough therapy: Jan 6,2013
2018 consensus sales: $2,446 million (Kalydeco)

On January 6, 2013, Vertex became the first company to receive the new breakthrough Therapy Designation. Kalydeco (Ivacaftor), the first available drug that targets the defective protein responsible for cystic fibrosis, was approved last year after a lightning-quick three-month review for the 4% of people with cystic fibrosis who harbor a G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and are older than 6. Vertex is now seeking to gain broader approvals for the use of Kalydeco (Ivacaftor) in younger children with the G551D mutation as well as those with other mutations that affect the CFTR protein in similar ways.

Kalydeco + Lumacaftor(VX-809)

Indication: Cystic fibrosis
Company:Vertex Pharmaceuticals
Current stage: Phase III
Expected launch:2014
Date announced for breakthrough therapy: Jan 6,2013
2018 consensus sales: $2,446 million (Kalydeco), $1,542 million (lumacaftor)

The U.S. Food and Drug Administration (FDA) has awarded Kalydeco (Ivacaftor) and Lumacaftor (VX-809) Breakthrough Therapy Designation. Vertex is advancing Kalydeco together with Lumacaftor(VX-809) for people with the most common type of cystic fibrosis mutation, known as F508del.

Ibrutinib (Imbruvica)

Indication: Relapsed/refractory mantle cell lymphoma (MCL)
Company:Pharmacyclics/Johnson & Johnson
Current stages: First Approved on November 13, 2013
Expected launch:2014
Date announced for breakthrough therapy: Feb 12, 2013
2018 consensus sales: $2,317 million

In February 12,2013, FDA granted Breakthrough Therapy Designations for oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib as a monotherapy for two B-cell malignancies: in patients with relapsed or refractory Mantle cell lymphoma (MCL) who have received prior therapy, and in patients with Waldenstrom’s macroglobulinemia (WM). On November 13, 2013, Ibrutinib (Imbruvica) became the second drug (Roche’s Obinutuzumab/Gazyva is the first) to be approved through FDA’s breakthrough therapy designation program for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Ibrutinib is jointly being developed by Janssen and Pharmacyclics Inc.

Ibrutinib (Imbruvica)

Indication: Waldenstrom’s macroglobunaemia
Company:Pharmacyclics/Johnson & Johnson
Current stages: II/III
Expected launch:2014
Date announced for breakthrough therapy:Feb 12, 2013
2018 consensus sales: $2,317 million

Ibrutinib (Imbruvica)

Indication: CLL/small cell lymphoma
Company:Pharmacyclics/Johnson & Johnson
Current stages: NDA/BLA
Expected launch:2014
Date announced for breakthrough therapy: April 8, 2013
2018 consensus sales: $2,317 million

Ibrutinib was granted on April 8, 2013 Breakthrough Therapy Designation as a monotherapy in the treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma with deletion of the short arm of chromosome 17 (del17p). Del17p is a genetic mutation that occurs in some patients with CLL/SLL; it is associated with a poor prognosis.

LDK378

Indication:ALK+ non-small-cell lung cancer
Company:Novartis
Current stage:Phase III
Expected launch:2015
Date announced for breakthrough therapy: March 15, 2013
2018 consensus sales: N/A

LDK378, a highly selective inhibitor of ALK, was granted “Breakthrough Therapy Designation” by the FDA in March for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have already received treatment with crizotinib (Xalkori).

Palbociclib

Indication: Breast cancer
Company:Pfizer
Current stage:Phase III
Expected launch:2015
Date announced for breakthrough therapy: April 10, 2013
2018 consensus sales: $1,197 million

One of Pfizer’s top late-stage breast cancer drug Palbociclib (formerly known as PD-0332991) is a novel oral selective inhibitor of cyclin-dependent kinase (CDK) 4/6 that prevents cellular DNA synthesis by blocking tumor cell progression. Novartis’rival drug LEE011, which its researchers are touting as the most selective CDK4/6 inhibitor to date, has quietly closed the gap and will enter Phase III in December 2013. Eli Lilly also has a CDK 4/6 drug LY2835219 in the pipeline.

Update:

On February 03, 2014, Pfizer announced that the randomized Phase 2 trial (PALOMA-1)of palbociclib achieved its primary endpoint by demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for the combination of palbociclib and letrozole compared with letrozole alone in post-menopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or newly diagnosed metastatic breast cancer. Pfizer has started two Phase III trials of the drug – Paloma-2 and Paloma-3 – in patients with advanced breast cancer.

Lambrolizumab(MK-3475)

Indication: Melanoma
Company: Merck & Co.
Current stage:Phase III
Expected launch:2015
Date announced for breakthrough therapy: April 24,2013
2018 consensus sales: $760 million

While it has not been a good year for Merck  as the company restructures when in October the company announced 8,500 more job cuts in addition to the 7,500 previously announced, it may have found its future billion dollar drug in its investigational anti-PD-1 lambrolizumab (formerly known as MK-3475).

Lambrolizumab (MK-3475) is currently in a phase II study versus traditional chemotherapy in patients who have progressed after prior therapy, as well as a phase III trial comparing it with Bristol-Myers Squibb’s CTLA-4 inhibitor Yervoy (ipilimumab), which is establishing itself as the second-line therapy of choice in advanced melanoma. Merck is vying with other drugmakers to bring the first anti-PD-1 therapy to market, notably BMS whose nivolumab candidate is in phase III; Roche which has MPDL3280A in phase II; and AstraZeneca, which has the anti-PD-1 drug AMP-514 in early-stage testing. Analysts estimate that nivolumab will reach market first with peak sales of around $1bn, while MK-3475 is expected to launch a little later with sales in the order of $500m a year.

Daclatasvir + Asunaprevir + BMS-791325

Indication: Hepatitis C
Company: Bristol-Myers Squibb
Current stage:Phase III
Expected launch:2016
Date announced for breakthrough therapy: April 25, 2013
2018 consensus sales: $1,224 million

Bristol-Myers Squibb’s interferon-free all-oral HCV triple Direct-Acting Antiviral (DAA) combination of Daclatasvir (BMS-650032, an NS5A inhibitor), Asunaprevir (BMS-650032,an NS3 protease inhibitor), and BMS-791325 (non-nucleoside NS5B polymerase inhibitor) received the FDA Breakthrough Therapy Designation on April 25, 2013.

The breakthrough designation also reflects a certain kind of vindication for BMS, which in August last year halted development of a hepatitis C drug BMS-986094 (INX-189) that it had acquired in a $2.5 billion deal from Inhibitex when nine participants in a clinical trial were hospitalized and one of them died.

SD-101

Indication: Epidermolysis bullosa (EB)
Company:Scioderm
Current stage:Phase II
Expected launch:N/A
Date announced for breakthrough therapy: April 29, 2013
2018 consensus sales: N/A

Scioderm’s investigational topical treatment SD-101 received in April 2013 Breakthrough Therapy designation from the FDA for the treatment of chronic wounds and lesions in children with various types of Epidermolysis Bullosa, commonly abbreviated as EB. SD-101 has also been designated as an orphan drug by the U.S. Food and Drug Administration for the treatment of Epidermolysis Bullosa (EB).

With skin as fragile as a butterfly wing, EB patients are sometimes referred to as “Butterfly Children”. Physical wounds on the skin prevent children from enjoying normal daily activities. The only current treatment for EB is daily wound care management and bandaging, and there is no cure for this disease.

Daratumumab

Indication: Multiple myeloma 3/4th line
Company:Genmab/Johnson & Johnson
Current stage:Phase II
Expected launch:2015/16
Date announced for breakthrough therapy: May 1, 2013
2018 consensus sales: $2 billion

Daratumumab is a human CD38 monoclonal antibody in clinical development for multiple myeloma (MM). Daratumumab has been granted Breakthrough Therapy Designation from the US FDA. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop and commercialize daratumumab. There are 2 other anti-CD38 antibodies in clinical development, MOR202 from Celgene  and Morphosys) and SAR650984 from Sanofi and Immunogen.

ABT-333 + ABT-333 + ABT-267

Indication: Hepatitis C
Company:AbbVie
Current stage:Phase III
Expected launch:Early 2015
Date announced for breakthrough therapy: May 6, 2013
2018 consensus sales: $1,994 million

AbbVie announces on May 6, 2013, that the FDA has given the Breakthrough Therapy Designation to the company’s non-orphan, interferon-free, all-oral triple Direct-Acting Antiviral (DAA) combination, with and without ribavirin, for genotype 1 (GT1) Hepatitis C (HCV). The triple Direct-Acting Antiviral (DAA) combo includes :

•   ABT-450/r (protease inhibitor and ritonavir)
•   ABT-267 (NS5A inhibitor)
•   ABT-333 (non-nucleoside polymerase inhibitor).

AbbVie is currently in later Phase III and on track for major regulatory submissions for the 3D regimen in the second quarter of 2014.

Gazyva (Obinutuzumab, GA101)

Indication: Chronic lymphocytic leukaemia
Company:Roche
Current stage: Approved on November 1, 2013
Expected launch:2014
Date announced for breakthrough therapy: May 15, 2013
2018 consensus sales: $1,405 million

On November 1, 2013, Roche’s Gazyva (obinutuzumab, aka GA101) became the first drug with breakthrough therapy designation to get greenlighted by the FDA in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CCL).

Sebelipase alfa (SBC-102)

Indication: Early onset Wolman disease
Company:Synageva BioPharma
Current stage:Phase III
Expected launch:N/A
Date announced for breakthrough therapy:  May 22, 2013
2018 consensus sales: N/A

Sebelipase alfa (SBC-102) is a recombinant form of the human LAL enzyme being developed by Synageva as an enzyme replacement therapy for early onset lysosomal acid lipase deficiency (LAL Deficiency), also known as Wolman disease.

Synageva is currently evaluating sebelipasealfa in global Phase 3 clinical trials in infants, children and adults with LAL Deficiency. Sebelipase alfa has been granted orphan designation by the U.S. FDA, the European Medicines Agency (EMA), and the Japanese Ministry of Health, Labor and Welfare. Additionally, sebelipase alfa received fast track designation by the FDA, and Breakthrough Therapy designation by the FDA for LAL Deficiency presenting in infants.

Asfotase alfa

Indication: Hypophosphatasia
Company: Alexion Pharmaceuticals
Current stage:Phase III
Expected launch:Late 2014
Date announced for breakthrough therapy: May 28, 2013
2018 consensus sales: $333 million

The rare diseases specialist Alexion Pharmaceuticals currently has one drug on the market in the form of Soliris (eculizumab), a treatment for the rare blood disorder paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemia syndrome (aHUS).  Soliris (eculizumab) is currently the most expensive drug in the world with an annual cost of around $440,000. Soliris sales topped $1.1bn in 2012.
One other enticing asset could however be asfotase alfa, an enzyme replacement for the inherited ultra-rare metabolic disorder hypophosphatasia (HPP) that was recently granted breakthrough status by the FDA and is in phase III testing, with NDA filings due next year.

Analysts have suggested that asfotase alfa could give the company a second big-selling product. Alexion acquired rights to asfotase alfa (formerly ENB-0040) when it bought Enobia Pharma last year for $610 million in cash plus $470 million in potential milestone payments.

Serelaxin (RLX030)

Indication: Acute heart failure
Company:Novartis
Current stage:Phase III
Expected launch:2014
Date announced for breakthrough therapy: June 21, 2013
2018 consensus sales: N/A

RLX030 (serelaxin), a recombinant form of a naturally occurring hormone (human relaxin-2), is an investigational treatment for patients with acute heart failure (AHF).

Results from the phase III RELAX-AHF clinical trial released in 2012 demonstrated inter alia that RLX030 reduced the risk of death by more than one-third compared with conventional treatment at six months.  Since then, Novartis has submitted serelaxin for approval with regulatory agencies around the world, and the US FDA has designated the drug a ‘breakthrough’ therapy. Novartis acquired Serelaxin when it bought Corthera in February 2010 for an upfront fee of $120m and around $500m in milestone payments.

Drisapersen

Indication: Duchenne muscular dystrophy
Company: GlaxoSmithKline/Prosensa
Current stage:Phase III
Expected launch:2014
Date announced for breakthrough therapy: June 27, 2013
2018 consensus sales: $138 million

Duchenne muscular dystrophy (DMD) is severely debilitating childhood neuromuscular disease that affects one in 3,500 live male births and is caused by mutations near exon 51 of the dystrophin gene.

Based on the positive results of a 53-patient phase II study in June 2013, the US Food and Drug Administration granted breakthrough therapy designation to Dutch biotech Prosensa and GlaxoSmithKline’s exon-skipping drug drisapersen (GSK2402968A) for the potential treatment of patients with Duchenne muscular dystrophy (DMD). But in September, the two companies announced that drisapersen did not meet the primary endpoint of improvement on the 6 minute walk test in a large-scale, phase 3 trial.The ultimate fate of the drisapersen program remains to be decided.

Sofosbuvir(Sovaldi) + Ledipasvir

Indication: Hepatitis C
Company:Gilead
Current stage:Phase III
Expected launch:N/A
Date announced for breakthrough therapy: July 25, 2013
2018 consensus sales:N/A

On December 6, 2013, Gilead’s Sofosbuvir (trade name:Sovaldi, formerly known as GS-7977, PSI-7977) became the third drug with breakthrough therapy status to be approved by FDA as part of a regimen for the treatment of chronic hepatitis C virus (HCV) infection caused by viruses of genotypes 1, 2, 3, or 4.

Sovaldi plus another antiviral pill ribavirin is the first all-oral regimen that does not require the injectable interferon to treat certain types (genotype 2 or genotype 3) of chronic HCV infection.

Next year Gilead expects to file for FDA approval of a combination pill with breakthrough designation containing sofosbuvir and ledipasvir that could become the first all-oral regimen for HCV genotype 1, the most common form of hepatitis C virus.

Almost 100% of the patients with hepatitis C infection achieved a sustained virologic response rate 12 weeks (SVR12) after completing treatment with a fixed-dose oral combination of sofosbuvir and ledipasvir (formerly GS-5885), with or without ribavirin, for 8 or 12 weeks, in a phase II LONESTAR study that enrolled previously untreated and treated patients. Phase III studies (ION-1, ION-2, and ION-3) are underway, and are evaluating 8, 12, and 24 weeks of treatment with the fixed-dose combination, with and without ribavirin, in treatment-naive and treatment-experienced individuals with HCV genotype 1.

Update (December 18, 2013): Two-drug Hepatitis C (sofosbuvir and ledipasvir)  combination cures 94% of genotype 1 patients in 8 weeks

A two-drug combination of sofosbuvir and ledipasvir cured 94% of previously untreated patients with genotype 1 hepatitis C infection after 8 weeks, without the need for ribavirin, Gilead Sciences announced on December 18, 2013. The results released come from one of three trials of the combination, ION-3. Two other studies tested the combination for longer periods and previously untreated and treatment-experienced patients, and showed similarly high cure rates after 12 or 24 weeks of treatment, with or without ribavirin. Gilead Sciences said that the very high cure rates observed in the studies mean that it will be possible to speed up registration plans for the combination. The company now plans to submit a new drug application in the first quarter of 2014, which means that the combination could receive marketing approval in the United States in the final quarter of 2014.

Update (February 10, 2014):

On February 10, 2014, Gilead submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval of a once-daily fixed-dose combination pill of Sofosbuvir (400 mg) and Ledipasvir (90 mg) for the treatment of patients with chronic hepatitis C genotype 1 infection. If approved, this fixed-dose combination would be the first interferon and rivavirin-free oral treatment regimen for patients with gentoype 1 HCV infection. The phase III studies showed efficacy of the combination within 8 weeks in refractory hepatitis C patients with cure rates up to 99%. Approval is largely expected from the FDA fro the breakthrough-designated drug with the treatment going to market this year.

Bimagrumab (BYM338)

Indication: Sporadic inclusion body myositis (sIBM)
Company:Novartis
Current stage:Phase II/III
Expected launch:Early 2015
Date announced for breakthrough therapy: August 20, 2013
2018 consensus sales:N/A

Bimagrumab (BYM338) is a novel, fully human monoclonal antibody developed to treat pathological muscle loss and weakness. Bimagrumab was developed by Novartis in collaboration with MorphoSys, whose HuCAL library was used to identify the antibody.

Bimagrumab binds with high affinity to type II activin receptors, preventing natural ligands from binding, including myostatin and activin. Novartis received FDA breakthrough therapy designation for bimagrumab for sporadic inclusion body myositis in August 2013. In addition to being developed in sporadic inclusion body myositis (sIBM), bimagrumab is in clinical development for chronic obstructive pulmonary disease (COPD), cancer cachexia, sarcopenia and in mechanically ventilated patients.

Amifampridine phosphate (Firdapse®)

Indication: Lambert-Eaton myasthenic syndrome
Company:Catalyst Pharma
Current stage:Phase III
Expected launch: N/A
Date announced for breakthrough therapy: August 27, 2013
2018 consensus sales:N/A

Marketed by BioMarin as the brand name Firdapse, Amifampridine Phosphate (3,4-diaminopyridine phosphate, 3,4-DAP phosphate) offers a crucial new hope for patients enduring the rare neuromuscular disorder Lambert-Eaton myasthenic syndrome (LEMS). In October 2012, Catalyst Pharma acquired the North American rights to Firdapse, a proprietary form of amifampridine phosphate from BioMarin Pharmaceutical Inc. On August 27, 2013 the FDA granted Amifampridine Phosphate a Breakthrough Therapy Designation.Amifampridine Phosphate has already approved in January 2010 in the EU to treat patients with Lambert-Eaton myasthenic syndrome.

Entinostat

Indication: Advanced breast cancer
Company: Syndax
Current stage:Phase II
Expected launch:Early 2015
Date announced for breakthrough therapy: September 11, 2013
2018 consensus sales:N/A

The novel HDAC inhibitor entinostat (also known as SNDX-275 and MS-275) from Syndax in combination with exemestane has received a Breakthrough Therapy designation from the FDA in September 11, 2013 for its potential to reverse resistance to hormonal therapies used to treat patients with advanced estrogen receptor (ER)-positive breast cancer.

On September 4, 2013, Syndax announced a licensing, development, and commercialization agreement with a specialty pharmaceutical company in China, Eddingpharm (亿腾医药). As part of this agreement, Eddingpharm was granted permission to participate in the first 3 global phase III registration trials for entinostat, which is being examined in a variety of other tumor types in addition to breast cancer.

Ofatumumab (Arzerra)

Indication:First-line Chronic lymphocytic leukemia (CLL)
Company: GlaxoSmithKline/Genmab
Current stage:sNDA/sBLA
Expected launch:N/A
Date announced for breakthrough therapy: September 13, 2013
2018 consensus sales: N/A

GlaxoSmithKline and Genmab’s Ofatumumab (trade name Arzerra, also known as HuMax-CD20) was approved by the FDA in 2009 for the treatment for chronic lymphocytic leukemia (CLL) patients who have not responded to Genzyme Corp’s Campath (alemtuzumab) or the chemotherapy fludarabine, and was also recently awarded ‘breakthrough therapy’ status by the regulator as a first-line treatment for the disease in September this year. Ofatumumab is a human monoclonal antibody that targets the CD20 protein, which is expressed on the surface of both normal and malignant B-cells. This mechanism of action allows for a greater response from the immune system against these cancerous cells.

Volasertib

Indication:Acute Myeloid Leukemia (AML) in patients over the age of 65
Company:Boehringer Ingelheim
Current stage:sNDA/sBLA
Expected launch:N/A
Date announced for breakthrough therapy: September 17, 2013
2018 consensus sales:N/A

The novel polo-like kinase 1(PLK1) inhibitor volasertib in combination with low-dose cytarabine (LDAC) received a Breakthrough Therapy designation in September 17, 2013 from the FDA for its potential as a treatment for patients aged 65 or older with untreated acute myeloid leukemia (AML) who are ineligible for intensive remission induction therapy.

Alectinib

Indication:ALK-positive NSCLC that is resistant to crizotinib
Company:Roche
Current stage:II
Expected launch:N/A
Date announced for breakthrough therapy: September 23, 2013
2018 consensus sales:N/A

The investigational second-generation ALK inhibitor Alectinib, which is being developed by Roche/Chugai Pharmaceutical, has already demonstrated an objective response rate of 93.5% in crizotinib (Xalkori)-naive ALK-positive non–small cell lung cancer. Based on the new data, alectinib was granted a breakthrough therapy designation by the Food and Drug Administration to expedite its development and review. Crizotinib (Xalkori) is the only approved ALK-inhibitor for use in ALK-rearranged non–small cell lung cancer; it is available for use in any line therapy in the United States and as second-line therapy only in Europe.

MK-5172 + MK-8742

Indication:Hepatitis C
Company:Merck
Current stage:II
Expected launch:N/A
Date announced for breakthrough therapy: October 22, 2013
2018 consensus sales:N/A

Merck hopes its MK-5172 can make its way to market as a successor to its marketed hepatitis C drug Victrelis (Boceprevir). In a small patient population, MK-5172, when combined with MK-8742, produced between a 96% and 100% cure rate during a Phase 2 (C-WORTHY) Study. That was good enough for the FDA to grant the combination coveted breakthrough status.  MK-5172/MK-8742 is an all-oral combination regimen consisting of MK-5172, an investigational HCV NS3/4A protease inhibitor, and MK-8742, an investigational HCV NS5A replication complex inhibitor.  But Merck’s MK-5172/MK-8742 combo is well behind a group of next-gen therapies from Gilead, AbbVie and Bristol-Myers Squibb that are all angling for near-term approvals.

ALXN1101 (cyclic pyranopterin monophosphate, cPMP)

Indication:Molybdenum cofactor deficiency type A
Company:Alexion
Current stage:II
Expected launch:N/A
Date announced for breakthrough therapy: October 24, 2013
2018 consensus sales:N/A

Alexion received its second breakthrough therapy designation from the FDA in October for ALXN1101 (cyclic pyranopterin monophosphate,cPMP) to treat patients with molybdenum cofactor deficiency (MoCD) type A, a fatal and ultra-rare genetic metabolic disorder which leaves newborns with catastrophic brain damage in the first weeks of life.

The drugmaker acquired the enzyme co-factor replacement treatment from Orphatec for $3 million plus milestones, putting the rare-disease treatment alongside the company’s Phase III asfotase alfa, which also received fast-track designation in May.

Andexanet Alfa (PRT4445)

Indication:Anticoagulant
Company:Portola
Current stage: Phase III
Expected launch:N/A
Date announced for breakthrough therapy: November 25, 2013
2018 consensus sales:N/A

Andexanet alfa (PRT4445) is a first-in-class recombinant, modified Factor Xa molecule that directly reverses the effects of Factor Xa inhibitors in patients who suffer an uncontrolled bleeding episode or who require emergency surgery.  Phase 2 proof-of-concept studies of andexanet alfa have been completed with apixaban (Eliquis, Pfizer  and BristolMyers Squibb) and rivaroxaban (Xarelto, Johnson & Johnson ). According to the company, Phase II results to date have shown andexanet alfa’s ability to immediately reverse the anticoagulant activity of Factor Xa inhibitors by the administration of a short intravenous bolus. Additional studies are being completed with enoxaparin and betrixaban, according to the company. Betrixaban is currently being studied in a Phase III clinical trial, and is claimed to have the potential to be the first oral Factor Xa inhibitor approved for venous thromboembolism (VTE) prevention in acute medically ill patients.

Tafenoquine

Indication:Plasmodium vivax malaria
Company:GlaxoSmithKline (GSK) and Medicines for Malaria Venture (MMV)
Current stage: Phase II
Expected launch:N/A
Date announced for breakthrough therapy: December 20, 2013
2018 consensus sales:N/A

GlaxoSmithKline and Medicines for Malaria Venture announced on December 20, 2013 that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for tafenoquine, an investigational medicine for the treatment and relapse prevention of Plasmodium vivax malaria.  Tafenoquine is not yet approved or licensed for use anywhere in the world.

Tafenoquine was first discovered by scientists at the Walter Reed Army Institute of Research in 1978 and is being developed in collaboration between GSK and MMV. Tafenoquine is being administered as a single dose during clinical trials in patients with P. vivax malaria. The Breakthrough Therapy designation was granted based on the results from an international, multicentre, randomised Phase II clinical trial in more than 300 patients with uncomplicated P. vivax malaria. Headline results from this trial were presented at the American Society of Tropical Medicine and Hygiene Meeting in November 2013, and detailed results published in The Lancet in December 2013. Plans are underway to start a Phase III study in 2014.

Tafinlar (dabrafenib)

Indication:non-small cell lung cancer with BRAF mutation
Company:GlaxoSmithKline (GSK)
Current stage: Approved on May 29, 2013 (US), August 26, 2013 (EU) as an oral treatment for unresectable melanoma or metastatic melanoma in adult patients with BRAF V600E mutation.
Date announced for breakthrough therapy: January 13, 2014
2018 consensus sales:N/A

The FDA has issued breakthrough therapy designation for GlaxoSmithKline’s Tafinlar(dabrafenib) on January 13, 2014 for treating patients with metastatic BRAFV600E mutation-positive non-small cell lung cancer who have received at least one prior platinum-containing chemotherapy.

On January 9, 2014, The FDA approved trametinib (Mekinist, GlaxoSmithKline) combined with Tafinlar(dabrafenib) for treatment of patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations. Tafinlar(dabrafenib) was approved on May 29, 2013 by the FDA as monotherapy for patients with metastatic or unresectable melanoma whose tumors express the BRAF V600E gene mutation.

Dabrafenib currently is not approved or licensed for treating NSCLC, and an estimated 2% of patients with NSCLC have the BRAF V600E mutation targeted by the drug, the release said.

Idelalisib (GS-1101,CAL-101)

Indication:relpapsed chronic lymphocytic leukemia (CLL)
Company:Gilead
Current stage: US NDA for CLL (December 6, 2013) and iNHL (September 11, 2013), EU MAA for CLL and iNHL (October 28, 2013)
Date announced for breakthrough therapy: January 13, 2014

Gilead’s Idelalisib is highly a selective inhibitor of PI3K-delta, an isoform found primarily in leukocytes. The molecule has a central role in activation, proliferation, migration, and survival of B lymphocytes. Gilead submitted the new drug application (NDA) for refractory indolent non-Hodgkin’s lymphoma (iNHL) to the FDA on September 11, 2013,  Idelalisib’s NDA for treatment of chronic lymphocitic leukemia (CLL) was submitted by Gilead on December 6, 2013. Following the submission of the NDA for iNHL, the FDA granted idelalisib a Breakthrough Therapy designation for treatment of patients with relapsed chronic lymphocytic leukemia (CLL). Gilead filed for approval in iNHL and CLL with the European Medicines Agency (EMA) on October 28, 2013.

Kalydeco + VX-661

Indication:cystic fibrosis (CF)
Company:Vertex Pharmaceuticals
Current stage: Phase II (expected during first half of 2014)
Date announced for breakthrough therapy:January 29, 2014

On January 29, 2014, Vertex announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for the combination of VX-661 and ivacaftor to treat people with cystic fibrosis (CF) who have two copies of the F508del mutation. Vertex has submitted a protocol to the FDA for a 12-week Phase 2 study to evaluate the safety, efficacy and pharmacokinetics of VX-661 in combination with ivacaftor. The company is currently finalizing the design of this study and expects to begin the study in the first half of 2014. The study will enroll people with two copies of the F508del mutation.

Eltrombopag – Promacta®(US)/Revolade®(Europe)

Trade Name:Promacta®(US), Revolade®(Europe)
Generic Name:Eltrombopag
Chinese Name:伊屈泼帕,艾曲泊帕
Indication:severe aplastic anaemia (SAA)
Company:GlaxoSmithKline,Ligand Pharmaceuticals
Current stage: Approved in the US for chronic immune (idiopathic) thrombocytopenic purpura (ITP) on November 20, 2008. Approved in the US for thrombocytopenia (low blood platelet counts) in patients with chronic hepatitis C on November 19, 2012
Date announced for breakthrough therapy: February 3, 2014GlaxoSmithKline and its partner Ligand Pharmaceuticals announced on February 3, 2014 that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for Promacta®/Revolade® (eltrombopag) for the treatment of cytopenias in patients with severe aplastic anaemia (SAA) who have had insufficient response to immunosuppressive therapy.  Eltrombopag is not approved or licensed anywhere in the world for use in this treatment setting. SAA is a rare disorder in which the bone marrow fails to make enough new blood cells. There are no approved therapies available for SAA patients unresponsive to initial immunosuppressive therapy (IST).  The Breakthrough Therapy designation was based on the results from an open-label, Phase II National Institute of Health (NIH) study (09-H-0154) of eltrombopag in 43 heavily pre-treated SAA patients with an insufficient response to IST.Ligand and its partner GlaxoSmithKline already market Promacta (Eltrombopag) to treat chronic hepatitis C and a rare condition called chronic immune thrombocytopenic purpura, in which the body attacks its own platelets.

Last Updated:February 7, 2014

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