Saturday, December 29, 2012

Pharma R&D Breakthroughs in 2012

Since last so many years, innovation in the pharma Industry has failed to impress stakeholders (patients, physicians and investors), but in 2012, we saw a trend that continued investment in new science and R&D has begun to deliver. Proof of concept data on new therapies in disease areas like Breast cancer, Cardiology, Diabetes, Ophthalmology, Lung cancer and Melanoma was presented at major conferences. These upcoming treatments have shown breakthrough improvement over current standard of care and could potentially transform the quality of life of patients going forward

1) FOVISTA (ANTI-PDGF)  IN PHASE 2 TRIALS BECAME THE FIRST THERAPY TO  SHOW BOTH DISEASE MODIFICATION AND SIGNIFICANT VISUAL GAIN IN THE MAJORITY OF PATIENTS WITH WET AMD  WHEN CO-ADMINISTERED WITH LUCENTIS.

Age Macular Degeneration (AMD) is a disease characterized by progressive degenerative abnormalities in the macula of the eye, a small area in the central portion of the retina. and has long been recognized as the leading cause of severe and irreversible loss of central vision in adults over the age of 50.  Wet AMD is a major unmet need as most patients fail to gain significant vision with monotherapy using an anti-VEGF agent (Lucentis / Eylea), the current standard of care.
In June 2012, Ophthotech Corporation reported its anti-platelet-derived growth factor (PDGF) agent, Fovista,  when administered in combination with Roche's Lucentis (ranibizumab) demonstrated robust  efficacy - A phenomenal 62 percent benefit over Lucentis alone. Lucentis targets VEGF, Fovista targets a different growth factor, PDGF. Since both of them promote the abnormal growth of new blood vessels under the retina, they deliver a double-whammy to wet AMD.

In the Phase 2b clinical trial involving 449 patients with wet AMD, Ophthotech’s Fovista ( anti-PDGF), administered in combination with Lucentis anti-VEGF therapy, met the pre-specified primary efficacy endpoint of mean vision gain. Patients receiving the combination of Fovista (1.5 mg) and Lucentis gained a mean of 10.6 letters of vision on the ETDRS standardized chart at 24 weeks, compared to 6.5 letters for patients receiving Lucentis monotherapy (p=0.019), representing a 62% additional benefits, which represents a paradigm shift in the treatment of wet AMD. 

2) ANTI-PD1 USHER IN HOPES OF REMISSION FOR CANCER PATIENTS

Unlike traditional chemotherapy, which affects the entire body, immunotherapy drugs only tracks down cancerous cells thus improving safety and efficacy. Designed on the same lines is BMY's anti-programmed death (PD)-1 monoclonal antibody BMS-936558 which has shown impressive activity in patients with melanoma, non-small-cell lung cancer (NSCLC), and renal cell cancer that has progressed despite standard therapy.
Early stage data points to the ability of this new drug to produce durable response and thus may transform the life of cancer patients.  
Phase 1 data on this  immuno-oncology pipeline candidate from Bristol-Myers  - BMS-936558 (anti-PD1, Programmed death 1 receptor blocker) was discussed at ASCO this year. The drug demonstrated objective response rates of 6%-32% in NSCLC, 19% to 41% in metastatic melanoma and 24%-31% in RCC.  In an initial trial of 240 patients, BMS-936558, shrunk tumors in 24 of 95 melanoma patients, 10 of 33 people with kidney cancer and 13 of 75 of those with advanced lung cancer.

3) SAR236553/REGN727 - PCSK9 ANTIBODY -  MAY FURTHER AID IMPROVEMENT IN CV OUTCOME FOR MILLIONS OF CORONARY ARTERY DISEASE PATIENTS

PCSK9 inhibitors are monoclonal antibodies directed against the protein PCSK9 which binds to LDL receptors on the liver. Phase 2 data presented this year at ACC Sanofi / Regeneron's SAR236553/REGN727 - PCSK9 Antibody demonstrated robust efficacy when  added to statins. SAR236553/REGN727 over 8 to 12 weeks significantly reduced mean low-density cholesterol (LDL-C, or "bad" cholesterol) by 40% to 72% in patients with elevated LDL-C on stable dose of statins.

According to Dr Steven Nissen (Cleveland Clinic, OH), the likelihood that PCSK9 inhibition approach to cut LDL is likely to be successful in improving CV outcome. It has been found that patients with genetic deficiencies in Pcsk9 were healthy and had a significantly lowered risk of developing coronary heart disease.

PCSK9 are a new class of drugs and are administered by subcutaneous injection weekly.  By not allowing binding of PCSK9 to the LDL receptor,  the LDL receptor is recycled to the surface after endocytosis, thereby effectively up-regulating the removal of LDL from the bloodstream by the liver. These drugs are administered by subcutaneous injection weekly and in early trials have been shown to demonstrably lower LDL levels.
The role of PCSK9 in lipid metabolism was discovered a few years ago based on population studies. Genetic data have shown that patients with natural loss-of-function mutations in PCSK9 have significantly lower LDL-C and a lower risk of coronary heart disease.

At ACC this year, Sanofi / Regeneron presented data on SAR236553/REGN727  from a Phase 2 dose finding study which enrolled 183 patients with elevated LDL-C (greater than or equal to 100 mg/dL) despite being on a stable dose of atorvastatin. The objective of the study was to evaluate the effect of adding SAR236553/REGN727 to existing statin therapy. 

The data showed that treatment with SAR236553/REGN727 over 8 to 12 weeks significantly reduced mean low-density lipoprotein-cholesterol (LDL-C, or "bad" cholesterol) by 40% to 72% in patients with elevated LDL-C on stable dose of statins

In another trial which enrolled patients with primary hypercholesterolemia with elevated LDL-C (greater than or equal to 100 mg/dL) who were on a stable low dose of atorvastatin (10 mg) with an objective  to compare the effect on LDL-C lowering of switching to a high dose of atorvastatin alone (80 mg) versus a high dose of atorvastatin combined with SAR236553/REGN727. Patients who received SAR236553/REGN727 plus atorvastatin 80 mg achieved a mean reduction of 73% in LDL-C, compared to a mean reduction of 17% for patients who switched to atorvastatin 80 mg alone (p < 0.001) after eight weeks. The study also included a third arm in which SAR236553/REGN727 was added to the stable low dose of atorvastatin. Patients in this arm achieved a 66% reduction in mean LDL-C. Patients in the study were followed for a total of 16 weeks for safety. 

4) T-DM1- A MIRACLE DRUG FOR HER2+VE BREAST CANCER

T-DM1 (trastuzumab emtansine) is a antibody-drug conjugate, consisting of a potent microtubule polymerization inhibitor conjugated to the trastuzumab monoclonal antibody via a highly stable linker.  It is developed by Roche in collaboration with Immunogen. T-DM1 is designed to take advantage of the targeted nature of the antibody to selectively deliver the cytotoxic agent to HER2+ breast cancer cells.  As a result T-DM1 does not show the typical side effects of chemotherapy because its small dose is mostly delivered selectively to the tumor site. 

In Phase 3 trial data presented this year T-DM1 has demonstrated not only strong efficacy but much lower rates of severe side effect, thus miraculously improving the quality of life for breast cancer patients.  Patients treated with T-DM1 lived an average of 5.8 months longer than those getting second-line standard of care Tykerb (lapatinib, GlaxoSmithKline plc) plus the chemotherapy Xeloda (capecitabine, Roche). The outcome was 30.9 months vs. 25.1 month. More importantly, TDM-1 also delivered patients a higher quality of life for a longer time. Patients treated wtih T-DM1 experenced much lower rates of  the painful  side effects – such as hair loss, black nails, peripheral neuropathy and/or constant fatigue associated with the existing standard of care.

Approximately 30% of patients in the traditional therapy arm stopped one or both drugs because of adverse events compared with 7% of patients in the T-DM1 arm. 


5) GSK - DABRAFENIB (BRAF INHIBITOR) AND TRAMETINIB (MEK INHIBITOR) - UNPRECEDENTED 12 MONTH SURVIVAL BENEFIT IN METASTATIC MELANOMA

Zelboraf (BRAF inhibitor) was recently approved for the treatment of metastatic melanoma patients with BRAF mutations. Although Zelboraf has demonstrated robust PFS benefit compared to dacrbazine, the overall impact on Overall survival was not as robust as majority of patients quickly develop resistance to BRAF inhibitors. 
In order to overcome this resistance, GSK has attempted a combination therapy (BRAF inhibitor + MEK inhibitor) that can help supress development of resistance. Results from a Phase 2 trial evalulating the combination of Dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) demonstrated the best PFS benefit observed from any therapy so far. 
Results from the study showed 61 percent of patients, in the combination arm, to have reduction in risk, resistance and death, with prolonged response averaging 9.4 months. 
Median follow-up was 14 months. Median progression-free survival was 9.4 months for the full-dose combination vs 5.8 months for the monotherapy arm (P < .0001), representing a 61% reduction in risk of disease progression. Median progression-free survival was 9.2 months for the arm using half-dose trametinib, which was also significantly better than monotherapy (P = .006). For every subgroup analyzed  (based on age, sex, baseline disease stage, baseline LDH, and presence of brain metastasis), the full-dose combination extended progression-free survival vs monotherapy.
The most significant statistic from the study was an increase from 33 percent of patients reaching the 12-month survival mark two years ago to 79 percent of patients reaching that mark today

 

6) ABRAXANE MAY IMPROVE SURVIAL IN PANCREATIC CANCER - A VALUE ADDED INNOVATION AFTER A LONG WAIT

Pancreatic cancer remains one of the most difficult cancers to treat, and innovating a drug that can extend surivival beyond the existing standard of care - Gemicitabine remains a challenge.  Gemcitabine, a strong chemotherapeutic agent, has been the standard of care in the first line setting  since 1997 despite a poor response and failure to improve survival rate.  

Almost 123,000 cases of pancreatic cancer are reported in US, Europe and Japan, out of which USA accounts for more than 43,000. In a large percentage of these, approximately 85%, resection is not possible either because the cancer is in stage III (locally advanced) or has metastasized (stage IV) at the time of diagnosis.

In the Phase 3 study, reported in November,  861 treatment-naive pancreatic cancer patients were randomized to treatment with Abraxane plus the chemotherapy gemcitabine or gemcitabine alone. The combination of Abraxane/gemcitabine demonstrated a statistically significant improvement in overall survival, the study's primary endpoint. Abraxane was well tolerated. Details from the study will be presented at a cancer research meeting in 2013. 
The Phase 3 study was powered to detect a statistically significant two month benefit in the pancreatic cancer population for Abraxane plus gemcitabine over gemcitabine alone. Historically, patients treated with  gemcitabine alone live about six months. 

7) ONCE WEEKLY ORAL DOSING MAY SOON BE A REALITY FOR TYPE 2 DIABETES PATIENTS

For the first time in history of new drug innovation in diabetes, we are closer to an oral drug that can be dosed as less frequently as once a week. At ADA 2012, Merck presented data on its once weekly DPP-IV inhibitor (MK-3102), which belongs to the same class as Januiva (sitagliptin), Onglyza (saxagliptin) but dosed once daily.

Phase 2 b data presented at EASD this year, showed that this once-weekly DPP-4 inhibitor significantly reduced HbA1c and a statistically significant trend was observed across doses studied for the secondary endpoints of 2-hour post-meal glucose and fasting blood glucose compared to placebo. The safety and tolerabiltiy profile as well was comparable to other once daily DPP-IV's on the market.

8) VEGF-B INHIBITION DEMONSTRATES POTENTIAL TO STOP PROGRESSION OF TYPE 2 DIABETES AND COULD EVEN REVERSE

Diabetes is growing pandemic and there is a desperate need for new treatment strategies for type II diabetes.   The current treatment for type II diabetes today involves initially placing the patient on a special diet; take daily pills which increase insulin secretion and also make the cells more sensitive to insulin. Occasionally they are given tablets to bring down the production of glucose. However, after a few years, for about one-third of all patients these treatments gradually lose their efficacy, and insulin injections are needed.
It was discovered way back in 1995 that by blocking VEGF-B, a signaling protein, fat does not accumulate in muscles and the heart, and the cells within those tissues can respond properly to insulin again. In 2012, we saw some proof of concept on this hypothesis, with Australia based biotech company CSL antibody drug 2H10 demonstrating benefit of inhibiting VEGFB. 

In one of the studies, diabetes-induced mice were given 2H10, a drug candidate which is an antibody that inhibits the actions of VEGF-B. The mice, which were specifically bred to spontaneously develop diabetes,  neither developed insulin resistance nor diabetes. The scientists crossed the mice with diabetes with mice that could not produce VEGF-B - they found that their pups never developed diabetes. Professor Ulf Eriksson and team carried out experiments on rats and mice, and managed to prevent type II diabetes from developing in the first place, as well as reversing disease progression in animals with established diabetes type II. Nature has described this finding as a "breakthrough in diabetes research".

In two different studies, rats and mice that had not been specifically bred to develop type II diabetes were used. These were fed a high-calorie, fat-rich diet and became obese. The animals' natural progression to diabetes was stopped, and also reversed to varying degrees after they were treated with 2H10.

9) PD 0332991 (PFIZER/ONYX) - FIRST IN CLASS CDK4/6 INHIBITOR MARKS THE DAWN OF A NEW ERA IN TREATEMENT OF POST MENOPAUSAL WOMEN WITH ER+VE /HER2BREAST CANCER

The current standard of care for post menopausal women diagnosed with metastatic breast cancer (ER+ve and HER2-ve) is aromatase inhibitors (Letrozole or Anasrazole). The typical median progression free survival observed with these therapies is 8-9 months. At SABCS this year, we got to see a data on a drug demonstrating unprecedented benefit when added to Letrozole compared to Letrozole alone in patients with post-menopausal patients with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer.

This drug from Pfizer - PD-0332991 (PD-991) in combination with letrozole significantly extended progression free survival (PFS) compared with letrozole alone.   

The magnitude of benefit demonstrated is phenomenal and has never seen before. Patients treated with the combination of PD-991 plus letrozole, median PFS was 26.1 months, a statistically significant improvement compared to the median PFS in women who received letrozole alone, which was 7.5 months (HR=0.37)


PD-991is CDK4/6 inhibitor designed to shut down retinoblastoma (Rb) phosphorylation, which drives cell division. With very favorable preclinical activity, CDK inhibitors have been on key opinion leaders’ radars recently as very promising agents, and the results from the randomized Phase II combining PD 0332991 with Femara (letrozole, Novartis) add to the enthusiasm.
Pfizer would be soon initiating a Phase 3 trial on this drug. 
We keep our fingers crossed that Safety does not play a spoilsport. 
The key limitation that can play a spoilsport despite the phenomenal efficacy is the safety events. The CDK inhibitor did add some significant hematologic toxicity. Rates of Grade 3/4 neutropenia were increased from 1% to 51% and leukopenia from 0% to 14%.  71% of patients required a dose interruption and 35% required a dose reduction; adverse events led to 10% of the discontinuations. As of now it appears that hematologic toxicity is significant but manageable. Ultimately, if the dramatic PFS benefit holds up in the Phase III study, physicians may be willing to deal with the toxicity.




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