Intarcia Therapeutics raises novel $225 million to develop exenatide pump

Intarcia Therapeutics has closed a $225 million financing in exchange for 1.5% of future global net sales of ITCA 650, a novel once or twice yearly exenatide pump. Investors have the option to convert their royalty interests into common stock in future.

Intarcia has raised over $1 billion since its founding. That includes a $225 million round today, a $50 million round in 2007, a $210 million round in 2012, a $200 million round in 2014, and $171 million upfront from Servier in 2014. Servier has rights to ITCA 650 outside of the U.S. and Japan.

ITCA 650 is a matchstick sized mini-pump which can be placed under the skin to release exenatide. Exenatide is a GLP-1 analog for the treatment of type 2 diabetes. A once-weekly injection has been approved under the trade name Bydureon.

ITCA 650 consists of a cylindrical titanium alloy reservoir. Once placed under the skin, water diffuses through a semi-permeable membrane into a salt osmotic engine at one end, which forces the drug to be steadily released at the other end. One of the main technical challenges was how to maintain the stability of exenatide at human body temperatures over long periods of time.

Intarcia is currently testing ITCA 650 in a Phase III program called FREEDOM. The company has completed two of the four Phase III trials in the FREEDOM program. Both the FREEDOM-1 and FREEDOM-1 HBL studies met their primary and secondary endpoints.

In the FREEDOM-1 trial, a mean reduction of 1.4% to 1.7% in HbA1c was observed across the majority of patients. The second trial, FREEDOM-1 HBL, showed a reduction of 3.4% in HbA1c in patients with very high baseline HbA1c levels (10-12%).

Catalyst Pharmaceutical shares plummet on competitor’s positive results

Catalyst Pharmaceutical (NASDAQ: CPRX) shares tumbled as much as 42% after Jacobus Pharmaceuticals, a competitor, disclosed positive results of 3,4-diaminopyridine (3,4-DAP, amifampridine) in patients with Lambert-Eaton myasthenic syndrome (LEMS) at the AAN2015 Annual Meeting.

LEMS is a rare autoimmune disease with a prevalence of 3000 patients in the U.S. and Canada. In LEMS patients, autoantibodies are formed against calcium channels, resulting in muscle weakness. Approximately 50% of LEMS patients have small cell lung cancer (SCLC) and will not survive for long.

3,4-DAP is recommended to improve LEMS symptoms. The compound blocks potassium channel efflux in nerve terminals so that calcium channels can be open for a longer time. In 2010 BioMarin Pharmaceutical (NASDAQ: BMRN) launched Firdapse (3,4-DAP phosphate) in the EU. Firdapse is the first and only approved drug for this indication.

In October 2012, BioMarin out-licensed North American rights of Firdapse to Catalyst. In August 2013, Firdapse received Breakthrough Therapy Designation from the FDA. In September 2014, Catalyst announced positive Phase III results. Catalyst expects an NDA submission to the FDA by 2015Q3. If approved, Firdapse may cost $60,000-80,000 per year, which would yield sales of $200 million.

For the past 20 years, Jacobus Pharmaceuticals, a family-owned pharmaceutical company has provided LEMS patients with 3,4-DAP for free in the U.S. under an FDA-approved compassionate use program. Compassionate use, also called expanded access, provides a pathway for patients to use investigational drugs that have not yet been approved by the FDA.

The company was founded by David Jacobus in 1977. About 20 years ago, Jacobus began to manufacture 3,4-DAP at the request of the Muscular Dystrophy Association. Jacobus sends 3,4-DAP to patients or their doctors every three months. The only thing Jacobus asks in return is that patients should mail back the ice packs used to protect 3,4-DAP.

Why supply 3,4-Dap for free? “Because supplying the drug for free is the right thing to do,” said Laura Jacobus. She also charged Catalyst with greed and indifference to LEMS patients. “They don’t want to help LEMS patients; they just want to make money.” Jacobus are conducting its own clinical trial to win FDA approval.

However, no one is perfect. The Jacobus compassionate use program can only reach 100-200 patients, which means most patients do not have access to treatment. Even more serious is the cGMP defects of Jacobus in the past. The FDA issued 483 inspection reports for the Jacobus facility in 2011 and again in 2012 (read them here and here).

Catalyst’s Firdapse contains the phosphate salt of 3,4-DAP. The phosphate salt form is more stable than the free base form of the 3,4-DAP that is available from Jacobus. Catalyst CEO Patrick McEnany stressed that their 3,4-DAP is produced under all requirements of cGMP. If there were an approved drug by the FDA, most patients would have easy access to this drug.

Catalyst and Jacobus are racing to get 3,4-Dap approved by the FDA. The winner will get seven years of orphan drug exclusivity in the U.S. and the loser would be frozen out.

MannKind inhaled insulin prescriptions show slight decline

About two months ago, Goldman Sachs analyst Jay Olson downgraded MannKind from Neutral to Sell with a revised price target of $3 from $6. I thought that four weeks wasn’t enough time to forecast sales. Patients usually need to wait three months or more to get an appointment with a doctor who can prescribe Afrezza.

Here is a look at Afrezza prescriptions through Week 13. Total prescriptions (TRx) for the week ending April 17 was 180 and new prescriptions (NRx) was 134, according to RBC Capital, citing data from IMS. NRx has declined since Week 11.

Afrezza has experienced a poor launch. MannKind shares are currently trading down about 40% from February. RBC Capital reduced Afrezza sales forecasts for 2015 to $5 million from $46 million. Afrezza is not the only inhaled insulin. Pfizer launched Exubera in 2006 and discontinued soon due to poor sales. If given time, can Afrezza be a big drug? That is the question.

questio

XBiotech is a biotech bubble

XBiotech (NASDAQ: XBIT) had a pretty good IPO, but I believe it is just a biotech bubble. The company is developing a cure-all for cancers, cachexia, vascular disease, type 2 diabetes, plaque psoriasis, and acne. Don’t expect any drug to be a cure-all.

XBiotech was founded by John Simard in 2005. Simard previously founded CTL ImmunoTherapies and AlleCure, which later merged to form MannKind (NASDAQ: MNKD). In total, XBiotech has raised $134 million since its founding.

The company believes its “True Human” mAbs have the potential to be safer and more effective than the currently marketed fully human mAbs. “True Human” means these mAbs are derived from a natural antibody identified from the blood of an individual.

MABp1 (Xilonix), XBiotech’s lead product candidate, is a anti-ILα mAb. IL1α is an inflammatory cytokine produced by leukocytes and other cells. Inflammation can indeed contribute to the development and progression of a variety of different diseases, but it doesn’t means blocking ILα can cure all these diseases. Antibodies against IL1α are expressed in about 10% of the healthy population. Schering-Plough abandoned their anti-IL1α program in 1994[1].

MABp1 has been administered to 170 patients in seven different clinical trials. In the 52-patient Phase I/II trial of MABp1 in metastatic cancer (18 tumour types), only one patient had a partial response[2]. XBiotech touts that patients receiving MABp1 live longer on average than historical controls, but I think the trial was too small to support the comparison.

XBiotech has completed a Phase II trial to test MABp1 in 7 patients with type 2 diabetes. After the 60 days period of treatment, HbAlc was reduced by 0.14±0.21%. The change was not statistically significant (p=0.15). Almost all approved diabetes drugs have produced significantly higher reductions in HbA1c levels.

In the Phase II study of MABp1 in 8 patients with moderate to severe plaque psoriasis[3], only one patient achieved a PASI score of 75 at week 8. According to the Humira (adalimumab) label, 71% of patients achieved a PASI 75 response at week 16.

XBiotech is testing MABp1 in colorectal cancer in two Phase III trials. The European trial will enroll at least 276 patients and is expected to be completed by mid-2015. The U.S. trial was designed for 656 patients. XBiotech amended the inclusion criteria and the control arm in 2014. The enrollment has resumed with a projected completion in 2016. Prior to the protocol amendment, 40 patients had entered the study. The findings were not statistically significant due to the relatively small number of patients.

In my opinion, it is reckless to initiate such a large Phase III trial without solid proof of concept. Adam Feuerstein at TheStreet had a negative comment as well:

XBiotech’s S-1 is filled with classic biotech red flags, including lack of quality venture capital backers, D-list underwriters and dubious clinical data generated from small subsets of patients presented in ways which overestimate treatment effect.

[1] Front Immunol. 2015, 6, 55.
[2] Lancet Oncol. 2014, 15(6), 656-666.
[3] JAMA Dermatol. 2015, doi: 10.1001/jamadermatol.2014.5391.

AACR Annual Meeting 2015 Highlights

Abstract#CT101
Pembrolizumab is better than ipilimumab as first-line therapy for patients with advanced melanoma. ORR was 33% for pembrolizumab and 12% for ipilimumab. The 6-month OS rates were 85-88% for pembrolizumab arms and 75% for ipilimumab.

Abstract#CT103
Pembrolizumab showed an ORR of 24% and a disease control rate of 76% in 25 patients with pleural mesothelioma. 80% 0f patients had received standard chemotherapy (platinum plus pemetrexed). There is no approved second-line treatment.

Abstract#CT104
The relationship between ORR and PDL1 expression was verified in patients with NSCLC. PFS and OS were longer in patients with membranous PDL1 expression in ≥50% of tumor cells (PS≥50%).

Abstract#CT105
According to the preliminary Phase I results of CART-meso, CAR-T therapy appears safe and feasible in advanced solid tumors. Anti-tumor efficacy was observed in 2 out of 5 patients.

Abstract#CT106
Immunocore’s TCR therapy, IMCgp100, showed an ORR of 25% (4/16) in patients with advanced melanoma. One partial response was observed in an ipilimumab refractory patient. Two of the partial responses have lasted more than 12 months.

Abstract#CT107
Atara Biotherapeutics presents Phase II clinical data of EBV-CTLs in patients with EBV-associated lymphoproliferative disorder (EBV-LPD). EBV-LPD is one of the most concerning complications of blood stem cell transplantation. In the two trails, 50-59% of patients had a complete response. Most importantly, 81% of patients had failed prior rituximab.

Abstract#CT137
Combining anti-CD40 mAb CP-870893 with anti-CTLA4 mAb tremelimumab improves response rates and overall survival in patients with metastatic melanoma. ORR was 27.3%, with mOS of 26.1 months.

Abstract#CT138
Combining mTORC1/2 inhibitor AZD2014 with paclitaxel showed better outcome in ovarian and lung cancer. Of 7 patients with heavily pre-treated ovarian cancer, 3 had partial responses. Of 5 squamous NSCLC pre-treated with docetaxel, 2 had partial responses.

Abstract#CT139
Chk1 inhibitor GDC-0425 may enhance gemcitabine efficacy in solid tumors with p53 mutation. The trial enrolled 40 patients with a variety of solid tumors. Three patients including one patient with p53 mutated triple-negative breast cancer (TNBC) had partial responses. The partial response in TNBC has lasted more than 10 months.

Abstract#CT231
In July 2014, Roche acquired Seragon Pharmaceuticals and its selective estrogen receptor degraders for $1.725 billion. Now, Roche provides Phase I results of GDC-0810 (ARN-810) in ER+/HER- metastatic breast cancer at AACR2015. In the trial, 13 of 31 (42%) patients achieved stable disease > 6 months.

Abstract#CT232
Adding a PI3K inhibitor to letrozole may restore the sensitivity of ER+ breast cancer to antiestrogen therapy. In the Phase Ib trial of BYL719, 26 patients with ER+/HER2- metastatic breast cancer refractory to previous endocrine therapy were accrued. 18 patients had prior aromatase inhibitor therapy. In the trial, 19% of patients experienced a partial response, and 43% of patients had stable disease.

Abstract#CT233
Combining mTORC1/2 inhibitor AZD2014 with fulvestrant showed clinical benefit for patients with ER+ metastatic breast cancer. In the 49 patients with measureable disease, 9 confirmed and 3 unconfirmed partial responses were observed. Of the 66 patients, 31 had clinical benefit.

Abstract#CT234
Merrimack Pharmaceuticals updates Phase I results of HER2-targeted liposomal doxorubicin in HER2 positive metastatic breast cancer. In patients treated with ≥30 mg/m2 MM-302 alone or in combination with trastuzumab, the response rate was 12% and median PFS was 7.6 months. Merrimack believes MM-302 plus trastuzumab is more effective than standard chemotherapy plus trastuzumab.

Abstract#CT322
Olaparib have anti-tumor activity in a sub-population of metastatic castration-resistant prostate cancer patients. In the TOPARP trial, patients who had failed prior docetaxel and abiraterone were treated with olaparib. Overall, 16 of 49 patients experienced a response. Mutations in DNA repair genes were detected in 15 of 49 patients. Among these 15 patients with mutations, 13 responded to olaparib.

Abstract#2859
Genentech’s anti-PDL1 mAb MPDL3280A showed clinical activity in patients with metastatic triple-negative breast cancer. Among 21 PDL1 positive (IHC2 or 3) patients, ORR was 24%, and the 24-week PFS rate was 33%.

Abstract#2860
Adding nivolumab to ipilimumab improved clinical response compared to ipilimumab alone in patients with advanced melanoma. In BRAF wild-type patients, ORR was 60% in the combination group vs. 11% in the ipilimumab group. A higher rate of adverse events was observed in the combination group compared to ipilimumab alone, leading to more frequent discontinuation. However, patients who discontinued the combination due to toxicity had a 67% response rate.

Abstract#4707
Adaptimmune presents preliminary results of TCR therapy targeting NY-ESO-1 in patients with synovial sarcoma. Of 8 patients whose follow-up is sufficient to assess response, 4 experienced objective responses (1CR, 3PR).

ImmuneXcite develops antibody-drug conjugates to activate immune cells against cancer

Both antibody-drug conjugates and cancer immunotherapies are hot approaches for the treatment of cancer. What if a new therapy combines these two technologies? ImmuneXcite is developing antibody-glucan conjugates, known as mAbXcite, to activate immune cells against cancer.

The mAbXcite technology came from Dr. Rubin-Bejerano, ImmuneXcite’s CSO, when she was studying how neutrophils recognize fungi. Neutrophils are the most common type of white blood cell in humans. They are the first-line killers of bacteria and fungi.

Rubin-Bejerano purified a unique polymer of glucose, known as β-1,6-glucan, from fungal cell walls[1]. Bate-1,6-glucan could be recognized by neutrophils, triggering a immune attack on fungi. The discovery of β-1,6-glucan means Rubin-Bejerano found a way to recruit and activate neutrophils.

Systemic activation of neutrophils could be dangerous. Rubin-Bejerano discussed her results with Prof. Daniel Kohane at Harvard University. Kohane suggested her attaching β-1,6-glucan to antibodies, the resulting molecule could recruit neutrophils in a targeted way. The idea represents a new approach in the field of cancer immunotherapy.

The appealing idea received financial support from angel investors. The new company raised $2.42 million as seed fund in January 2012. In January 2014, ImmuneXcite secured $3.58 million in second-round financing. Dr. Alan Smith, former Genzyme CSO, joined the company’s scientific advisory board.

ImmuneXcite reports new preclinical data at the AACR2015. mAbXcite-cetuximab demonstrates significantly greater efficacy than the original antibody. Mice that show complete regression do not develop new tumors when cancer cells were reintroduced, suggesting a lasting immune response.

[1] Cell Host Microbe. 2007, 2(1), 55-67.

Rethink Celladon Corporation: high-risk, high-reward

I first wrote about Celladon Corporation (NASDAQ: CLDN) on March 19, 2015. I highlighted the amazing data of CUPID 1 trial and the low bar for the primary endpoint of CUPID 2. The Breakthrough Therapy designation further confirmed the blockbuster potential of Celladon’s gene therapy MYDICAR.

I recently noted several red flags in the CUPID 1 trial.

	Placebo (n=14)	Low Dose (n=8)	Mid Dose (n=8)	High Dose (n=9)
Age, mean	61.0	60.3	63.9	56.6
Sex, Female	1	1	0	3
NT-proBNP	4072	1353	3310	2141
Risk reduction		60% (p=0.11)	54% (p=0.12)	88% (p=0.03)

1. The patients in the high dose group were 4 years younger than the patients in the placebo group[1]. Moreover, the high dose group enrolled more female subjects. It is known that heart failure risk increases with age and men have higher hospitalization rates for heart failure[2].

2. The patients in the high dose group were significantly healthier than the patients in the placebo group. Higher NT-proBNP levels in the placebo group indicated worse outcomes. The levels of NT-proBNP are elevated in patients with left ventricular dysfunction[3].

3. Left ventricular ejection fraction (LVEF) did not increase appreciably in any group. If MYDICAR had restored contractility of the heart muscle, we should have observed that LVEF improved significantly in the high dose group.

4. In the low dose and mid dose group, risk reduction was not statistically significant. Patients with the mid dose of Mydicar performed worse than the low dose. The absence of a dose-dependent response raises concerns about the trial.

5. In the CUPID 1 follow-up, persistent presence of the SERCA2a transgene in cardiac tissue was detected in three of four high dose patients[4]. However, whether the amount of SERCA2a genes is sufficient to produce higher levels of SERCA2a protein and futher result in risk reduction are unclear.

I still believe in Celladon and its breakthrough gene therapy because the the primary endpoint bar is really low and the SERCA2a gene had been taken up by the heart muscle cells indeed, but we should know about the risks and rationally evaluate the risk/reward.

[1] Circulation. 2011, 124(3), 304-313.
[2] J Card Fail. 2013, 19(8), 542-549.
[3] Congest Heart Fail. 2004, 10(1 Suppl 1), 23-27.
[4] Circ Res. 2014, 114(1), 101-108.

Investigators report Phase I results of CAR-T therapy in solid tumors

Investigators of the University of Pennsylvania report Phase I results of CAR-T therapy in solid tumors at AACR2015. The therapy appears safe in the patients treated so far, but the anti-tumor efficacy was not good as expected.

The CAR-T therapy, known as CART-meso, targets mesothelin, a antigen present on normal mesothelial cells and overexpressed in several tumors.

In the study, five patients with recurrent advanced solid tumors (2 ovarian, 2 epithelial mesothelioma, and 1 pancreatic) were treated with a single infusion of 1-3×10^7 CART-meso cells.

CAR-T cells were found to traffic to tumor sites as well as to off-tumor on-target sites, but no off-tumor on-target toxicities was observed. CAR-T cells were detectable in the blood stream in all patients up to Day 21-28 after infusion.

Anti-tumor efficacy was suggested by the clearing of cancer cells in the pleural fluid of one patient. There was clinical evidence of stable disease in another patient.

The results were not good as expected. In previous studies, CD19 CAR-T therapy showed a complete response rate of 90% in relapsed and refractory ALL[1,2].

The dosages in the solid tumors study were relatively lower than the dosages in the previous ALL trials. The peak levels of CART-meso in blood were about 2 orders of magnitude lower than CART19. Mesothelin is also found in normal tissue, thereby high dose of CAR-T may damage healthy tissue.

It’s not always easy to find a perfect CAR-T target like CD19. Although CD19 is also found in normal B cells and CAR-T therapy may deplete normal B cells, patients can live with B cell depletion for a prolonged period. Further, CD19 is not expressed on hematopoietic stem cells, and therefore B cells should return after the CAR-T treatment.

Aduro Biotech (NASDAQ:ADRO) is developing a mesothelin vaccine, known as CRS-207, for the treatment of pancreatic cancer and mesothelioma. In the Phase IIa trial in pancreatic cancer, CRS-207 plus GVAX demonstrated a statistically significant improvement in overall survival (6.1 vs. 3.9 months)[3]. Based on the results from the Phase IIa trial, CRS-207 was granted Breakthrough Therapy designation by the FDA.

[1] N Engl J Med. 2014, 371(16), 1507-1517.
[2] https://ash.confex.com/ash/2014/webprogram/Paper76573.html
[3] J Clin Oncol. 2015, 33(12), 1325-1333.

Innocrin Pharmaceuticals raises $28 million to develop best-in-class CYP17 inhibitor

Innocrin Pharmaceuticals has completed a $28 million Series D financing round led by Eshelman Ventures and Fred Eshelman with participation of Novartis Venture Fund, Lilly Ventures, Hatteras Venture Partners, Intersouth Partners, and A&B Equity Holdings.

Innocrin is a spin-out of Viamet Pharmaceuticals. The company is developing a CYP17 inhibitor, VT-464, for the treatment of castration-resistant prostate cancer (CRPC). CYP17 is a validated target for the treatment of CRPC. Johnson & Johnson’s Zytiga (abiraterone acetate), an approved CYP17 inhibitor, generated annual sales of $2.24 billion in 2014. Innocrin believes VT-464 is a best-in-class CYP17 inhibitor.

CYP17 is a protein with two enzymatic functions: 17α-hydroxylase and 17,20-lyase. Lyase inhibition reduces the biosynthesis of androgens that drive cancer cell growth. However, hydroxylase inhibition elevates progestogens and mineralocorticoids, resulting in secondary mineralocorticoid excess. VT-464 is the most lyase-selective CYP17 inhibitors reported to date.

	lyase IC50 (nM)	hydroxylase IC50 (nM)	h/l ratio	Ref
abiraterone	15	2.5	0.17	[1]
VT-464	69	670	9.7	[1]
galeterone	23	73	3.2	[2]

Interim results from the Phase I/II trial (INO-VT-464-CL-001) were presented at the ASCO2015 Genitourinary Cancers Symposium[3]. 73% of treatment-naïve patients received 300-600 mg BID VT-464 had PSA30 responses. PSA responses were observed in 2 of 7 patients who have failed Xtandi (enzalutamide) as well.

Abiraterone has been shown to cause mineralocorticoid excess syndrome characterized by hypokalemia (88%), hypertension (40%), and fluid overload (31%)[4]. No mineralocorticoid excess syndrome was observed in the VT-464 Phase I/II trial.

Meanwhile, Tokai Pharmaceuticals (NASDAQ: TKAI) is developing a selective CYP17 lyase inhibitor known as galeterone. The company announced positive interim results from the phase II trial (ARMOR2) of galeterone in June 2014. Similarly, 82% of treatment-naïve patients achieved PSA30 responses. Tokai anticipates initiating the pivotal clinical trial in 2015H1.

[1] Bioorg Med Chem Lett. 2014, 24(11), 2444-2447.
[2] Cancer Research. 2013, doi: 10.1158/1538-7445.AM2013-83.
[3] J Clin Oncol. 2015, 33, (suppl 7; abstr 187).
[4] J Clin Oncol. 2009, 27(23), 3742-3748.

Edge Therapeutics raises $72.5 million to develop nimodipine microparticle

Edge Therapeutics raised $72.5 million through Series C-1 and C-2 financings. The $56 million C-2 round was led by Venrock with participation of Sofinnova Ventures, Janus Capital Management, Franklin Advisors, New Leaf Venture Partners and BioMed Ventures.

The company was established in 2009. The former CEO of Celgene, Dr. Sol Barer, is the current Board Chairman. Dr. Robert Langer, the most prolific inventor in medicine, has served as chair of Scientific Advisory Committee.

Edge is developing novel formulations of existing drugs with its Precisa platform. The foundation of Precisa is a biodegradable polymer called PLGA which can break down into lactic acid, releasing drugs slowly. Lupron Depot, an approved prostate cancer drug, uses PLGA to control the release profile of leuprolide as well.

Edge’s lead product candidate, EG-1962, is a PLGA-based nimodipine microparticle to prevent secondary strokes after subarachnoid hemorrhage (SAH). Patent WO2014164904 has disclosed the compositions of EG-1962.

SHA is usually caused by a ruptured brain aneurysm. Brain aneurysm can be treated with surgery, but the delayed strokes are more difficult to control. Current treatment guidelines recommend SAH patients to receive nimodipine every four hours over a 21-day period.

Nimodipine is a dihydropyridine calcium channel blocker which inhibits contractions of vascular
smooth muscle. When given orally or intravenously, nimodipine causes low blood pressure in 5% of patients, which should be carefully monitored in the treatment.

EG-1962 can be placed in the brain after surgery, locally releasing nimodipine over the course of 21 days. The microparticles sustain a high concentration of nimodipine in the brain and avoid systemic side effects including hypotension at the same time.

EG-1962 is currently in a Phase I/II trial (NEWTON). In February 2015, Edge reported initial data from the trial. The 90-day favorable outcome rate for patients treated with EG-1962 was 61% (n=11/18) vs. 17% (n=1/6) for oral nimodipine.

Hypotension has not been observed among any patients who received EG-1962 in the first three cohorts (n=27). By contrast, 33% of the nine patients treated with oral nimodipine experienced hypotension.

These results are consistent with the original hypothesis. Edge plans to provide top-line results from the NEWTON in 2015H1 and to initiate Phase III trials in 2015H2.

Furthermore, Edge’s second product candidate, EG-1964 (aprotinin filament), will enter clinical trials in 2015 to prevent recurrent bleeding after subdural hematoma (SDH).