Stem Cell Clinic

Chimerix Antiviral Compound, CMX001, Meets CMV Phase 2 Primary Endpoint in Allogeneic Hematopoietic Stem Cell …

RESEARCH TRIANGLE PARK, N.C., Feb. 6, 2012 /PRNewswire/ -- Chimerix, Inc., a biotechnology company developing novel antiviral therapeutics, today announced positive results from CMX001 Study 201, a Phase 2 study evaluating CMX001 for the prevention of cytomegalovirus (CMV) disease in hematopoietic stem cell transplant (HCT) recipients. CMX001 is a broad spectrum Lipid-Antiviral-Conjugate completing Phase 2 clinical development for the prevention of CMV in HCT recipients. In CMX001 Study 201, a double-blind, placebo-controlled trial which enrolled 230 HCT recipients, CMX001 had a statistically significant benefit versus placebo in preventing CMV viremia and/or CMV disease 13 weeks post-transplant.

Francisco Marty, MD, Assistant Professor of Medicine at Dana-Farber Cancer Institute and Brigham and Women's Hospital's Division of Infectious Disease, and a lead investigator in Chimerix's CMX001 Phase 2 CMV study, presented the data during the "Best Abstracts Plenary Session" at the 2012 BMT Tandem Meetings on February 3, 2012 in San Diego, California. "This study provides positive data supporting the antiviral activity of CMX001 at different dose levels, and a better understanding of CMX001's safety and tolerability as a prophylactic agent against CMV infection, a major cause of morbidity and mortality in bone marrow transplant recipients," said Dr. Marty.  "There is a substantial unmet medical need for safer and effective therapies against CMV. If approved, many patients have the potential to benefit from the future availability of CMX001."

"These results exceeded our high expectations, and we are thrilled to share such positive CMX001 data with the transplant community," said Wendy P. Painter, MD, MPH, Chimerix's Chief Medical Officer. "We look forward to initiating the Phase 3 CMV program later this year. This study reinforces our belief that CMX001's broad spectrum application against multiple viral infections, its safety profile and convenient oral dosing will enable it to become a new standard of care for transplant recipients." 

CMX001 Study 201 Results Presented at BMT Tandem Meetings

Results from subjects receiving CMX001 100 mg twice weekly met the primary endpoint, a statistically significant reduction in CMV viremia (CMV > 200 copies/mL) or disease at the end of treatment in CMX001-treated subjects versus those who received placebo (p=0.001). Moreover, CMX001 Study 201 showed that three different doses of CMX001 demonstrated statistically significant reductions in the proportion of subjects with CMV viremia ? 1000 copies/mL at any time during treatment when compared to placebo (p=0.002, <0.001, <0.001, respectively; see Table 1 below). In subjects who were CMV viremia negative prior to treatment, four different CMX001 dose regimens demonstrated statistically significant reduction versus placebo (see Table 2 below).

Table 1
Subjects with Clinically Relevant CMV Viremia
(> 1,000 copies/mL at any time during treatment)

Dose

Enrolled (N)

CMV Viremia (N)

%

P

40 mg QW(1)

25

10

40%

0.43

100 mg QW

27

6

22%

0.06

200 mg QW

39

7

18%

0.002

200 mg BIW(2)

30

2

7%

< 0.001

100 mg BIW

50

4

8%

< 0.001

Pooled Placebo

59

25

42%

-

(1)QW: Once weekly. (2)BIW: Twice weekly.

Table 2
Subjects with Clinically Relevant CMV Viremia – CMV Negative Strata
(> 1,000 copies/mL at any time during treatment)

Dose

Enrolled (N)

CMV Viremia (N)

%

P

40 mg QW

18

4

22%

0.55

100 mg QW

23

2

9%

0.04

200 mg QW

29

2

7%

0.02

200 mg BIW

22

0

0

0.002

100 mg BIW

41

0

0

< 0.001

Pooled Placebo

48

15

31%

-

There was no difference versus placebo across CMX001 treatment groups in measurements of renal function and hematologic parameters. Diarrhea was the most common adverse event seen in the CMX001 treatment groups and was dose-limiting at the highest dose of CMX001 (200 mg twice weekly).

CMX001 Study 201 Design

CMX001-201 was a randomized, double-blind, placebo-controlled, dose-escalation, multi-center trial evaluating the safety, tolerability, and ability of CMX001 to prevent or control CMV disease in 230 evaluable CMV seropositive allogeneic stem cell transplant recipients.  Following engraftment (Days 14-30 post-transplant), subjects were stratified based on the presence or absence of acute GVHD requiring systemic therapy and the presence or absence of CMV DNA in plasma and randomized (3:1, CMX001 versus placebo) into five sequential, dose-escalating cohorts. Subjects were treated once weekly or twice weekly for 9 to 11 weeks through post-transplant Week 13, after which subjects were followed for an additional 4 to 8 weeks. Placebo patient results were pooled for endpoint analysis.

About CMX001

CMX001 is a Lipid-Antiviral-Conjugate that delivers high intracellular levels of the active antiviral agent cidofovir-diphosphate and has broad spectrum in vitro activity against double-stranded DNA (dsDNA) viruses. CMX001 is completing Phase 2 clinical development for the prophylaxis of CMV and is in Phase 2 development for the preemption and treatment of adenovirus infection in HCT recipients. Antiviral activity results from completed and ongoing studies, coupled with the lack of myelotoxicity and nephrotoxicity seen in currently available therapies, indicate that CMX001 has the potential to improve outcome for immunosuppressed patients.

To date, more than 700 patients have been dosed with CMX001 in placebo-controlled clinical trials and open-label treatment protocols. As part of Chimerix's open-label treatment protocols, data were recently presented at ICAAC 2011[1] in an oral presentation entitled "CMX001 is not nephrotoxic or myelosuppressive in 183 patients with life threatening dsDNA infections including refractory Cytomegalovirus, Adenovirus, and BK Virus".

About Cytomegalovirus

CMV is a member of the herpesvirus group of dsDNA viruses. Like other herpesviruses, CMV has the ability to remain dormant in the body for long periods of time. In immunocompromised individuals, including transplant recipients, cancer patients and children born with primary CMV infection, CMV can lead to serious disease or death. At least 65% of transplant recipients are at moderate-to-high risk of CMV due to reactivation of latent virus from donor or recipient tissues. In these patients, CMV disease can lead to severe and potentially life-threatening conditions such as nephritis, pneumonitis or hepatitis, or complications such as acute or chronic rejection of a transplanted organ. While currently available systemic anti-CMV agents can be effective against the virus, their use is limited by significant toxicities, including myelotoxicity and nephrotoxicity.

About Chimerix

Chimerix is developing novel antiviral therapeutics with the potential to transform patient care in multiple settings, including transplant, oncology, acute care and global health. Utilizing proprietary lipid conjugate technology, the company's two clinical stage compounds have demonstrated the potential for enhanced activity, bioavailability and safety compared to currently approved drugs. 

In addition to the company's development of its lead candidate, CMX001, for transplant recipients, CMX001 is also being developed as a medical countermeasure in the event of a smallpox release, with the potential to provide an important therapeutic option for the 80 million people in the U.S. currently estimated to be immunocompromised, or a household contact of a contraindicated individual, and thus not candidates to receive a smallpox vaccine (for additional information, please see http://www.bt.cdc.gov/agent/smallpox/vaccination/contraindications-clinic.asp). Chimerix has received federal funding for the development of CMX001 as a medical countermeasure against smallpox from the National Institute of Allergy and Infectious Diseases under Grant No. U01-A1057233 and from the Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, under Contract No. HHSO100201100013C. 

Chimerix's second clinical-stage antiviral compound, CMX157, is a Lipid-Antiviral-Conjugate that delivers high intracellular levels of the active antiviral agent tenofovir-diphosphate. CMX157 is in development as a potent nucleoside analogue against HIV and HBV infections, and has the potential to directly address several limitations of current therapies. CMX157 has completed a Phase 1 clinical trial in healthy volunteers, providing pharmacokinetic data which support the compound's enhanced characteristics. 

Led by an experienced antiviral drug development team, Chimerix is also leveraging its lipid conjugate technology and extensive chemical library to pursue new treatments for hepatitis C virus, influenza, and other areas of high unmet medical need. For additional information on Chimerix, please visit http://www.chimerix.com.&nbsp;

[1] Genovefa Papanicolau, MD, Associate Member of Infectious Diseases Service at Memorial Sloan-Kettering Cancer Center, at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Annual Meeting, 2011.

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Chimerix Antiviral Compound, CMX001, Meets CMV Phase 2 Primary Endpoint in Allogeneic Hematopoietic Stem Cell ...

Macular Damaged Vision Improved with Stem Cells

Research using stem cells continues to be a controversial issue. But controversial or not, stem cell therapy use continues and new developments using the therapy to reverse vision loss are reported regularly. Keeping up with new improvements for reversal of vision loss for a person dealing with a vision issue is important. The idea of regaining vision offers hope to a person who lives with a vision impairment or blindness.

Researchers have reported vision loss improvement from a study using stem cells. Two women with different types of macular degeneration were treated with stem cell therapy. The first subject was a woman aged 70 with the dry form of aged related macular degeneration. The second subject was a woman aged 50 with Stargardt?s Macular Dystrophy.

The subjects were treated using 50,000 stem cells that were injected into one eye of each patient. The subjects were treated with eye therapy and followed for the next four months. During the four month time patients received eye therapy and eye exams. The vision of the first subject was improved by ten letters on a macular degeneration eye chart. The second subject ability to see movement improved and patient was able to see and count fingers correctly during hand movement tests. Researchers reported patients showed no signs of rejection or other difficulties during the stem cell trial.

What is macular degeneration?
The macular is the central part of the eye?s retinal nerve and is responsible for clarity and detail of central vision. Macular degeneration essentially, is the blocking of vision from debris in the eye or collection of fluid from leakage of abnormal growth of the blood vessels around the central part of the eye.

What are the different types of macular degeneration?
The disease is classified as wet or dry macular degeneration. The Dry form of the disease occurs when central vision damaged occurs from debris called drusen. Drusen shows up as yellow spots in the eyes. The drusen is thought to be material from deteriorating tissue.

Wet macular degeneration occurs when new blood vessels abnormally develop under the retina. The blood vessels begin to leak blood and fluid that collects around the macular causing damage and vision loss.

What are the risk factors?
1. Senior citizens Ages 60 and above
2. Smokers
3. Obesity
4. Race - White females have the highest number of cases

What treatments are available?
1. Wet Macular Degeneration
a. Drug injections
b. Laser surgery
c. Photodynamic therapy

2. Dry macular degeneration
a. Vitamins containing high levels of specific types of antioxidants
b. Balanced diet containing dark green leafy vegetables
c. Exercise

What are the symptoms?
1. The person may experience items such as; blurriness, squiggle or wavy lines and blind spots.
2. The faces of people seem wavy.
3. Doorways look crooked.
4. Objects look closer or farther away than normal

Medical research offers a visually disabled individual the hope of regaining vision. Staying informed and up to date on medical breakthroughs should be on the list of things to do for the visually disabled.

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Macular Damaged Vision Improved with Stem Cells

Key finding in stem cell self-renewal

ScienceDaily (Feb. 6, 2012) — A University of Minnesota-led research team has proposed a mechanism for the control of whether embryonic stem cells continue to proliferate and stay stem cells, or differentiate into adult cells like brain, liver or skin.

The work has implications in two areas. In cancer treatment, it is desirable to inhibit cell proliferation. But to grow adult stem cells for transplantation to victims of injury or disease, it would be desirable to sustain proliferation until a sufficient number of cells have been produced to make a usable organ or tissue.

The study gives researchers a handle on how those two competing processes might be controlled. It was performed at the university's Hormel Institute in Austin, Minn., using mouse stem cells. The researchers, led by Hormel Institute Executive Director Zigang Dong and Associate Director Ann M. Bode, have published a report in the journal Nature: Structure and Molecular Biology.

"This is breakthrough research and provides the molecular basis for development of regenerative medicine," said Dong. "This research will aid in the development of the next generation of drugs that make repairs and regeneration within the body possible following damage by such factors as cancer, aging, heart disease, diabetes, or paralysis caused by traumatic injury."

The mechanism centers on a protein called Klf4, which is found in embryonic stem cells and whose activities include keeping those cells dividing and proliferating rather than differentiating. That is, Klf4 maintains the character of the stem cells; this process is called self-renewal. The researchers discovered that two enzymes, called ERK1 and ERK2, inactivate Klf; this allows the cells to begin differentiating into adult cells.

The two enzymes are part of a "bucket brigade" of signals that starts when a chemical messenger arrives from outside the embryonic stem cells. Chemical messages are passed to inside the cells, resulting in, among other things, the two enzymes swinging into action.

The researchers also discovered how the enzymes control Klf4. They attach a small molecule--phosphate, consisting of phosphorus and oxygen--to Klf4. This "tag" marks it for destruction by the cellular machinery that recycles proteins.

Further, they found that suppressing the activity of the two enzymes allows the stem cells to maintain their self-renewal and resist differentiation. Taken together, their findings paint a picture of the ERK1 and ERK2 enzymes as major players in deciding the future of embryonic stem cells--and potentially cancer cells, whose rapid growth mirrors the behavior of the stem cells.

Klf4 is one of several factors used to reprogram certain adult skin cells to become a form of stem cells called iPS (induced pluripotent stem) cells, which behave similarly to embryonic stem cells. Also, many studies have shown that Klf4 can either activate or repress the functioning of genes and, in certain contexts, act as either an oncogene (that promotes cancer) or a tumor suppressor. Given these and their own findings reported here, the Hormel Institute researchers suggest that the self-renewal program of cancer cells might resemble that of embryonic stem cells.

"Although the functions of Klf4 in cancer are controversial, several reports suggest Klf4 is involved in human cancer development," Bode said.

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The above story is reprinted from materials provided by University of Minnesota.

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Journal Reference:

Myoung Ok Kim, Sung-Hyun Kim, Yong-Yeon Cho, Janos Nadas, Chul-Ho Jeong, Ke Yao, Dong Joon Kim, Dong-Hoon Yu, Young-Sam Keum, Kun-Yeong Lee, Zunnan Huang, Ann M Bode, Zigang Dong. ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4. Nature Structural & Molecular Biology, 2012; DOI: 10.1038/nsmb.2217

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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Key finding in stem cell self-renewal